Archive for the ‘Bone Marrow Stem Cells’ Category

NEW YORK, March 10, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited(Nasdaq: MESO; ASX:MSB) today announced that it plans to evaluate its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in patients with acute respiratory distress syndrome (ARDS) caused by coronavirus (COVID-19) in the United States, Australia, China and Europe. The Company is in active discussions with various government and regulatory authorities, medical institutions and pharmaceutical companies to implement these activities.

Mortality in COVID-19 infected patients with the inflammatory lung condition acute respiratory distress syndrome (ARDS) is reported to approach 50%, and is associated with older age, co-morbidities such as diabetes, higher disease severity, and elevated markers of inflammation.1 Current therapeutic interventions do not appear to be improving in-hospital survival.1

Remestemcel-L has potential for use in the treatment of ARDS, which is the principal cause of death in COVID-19 infection.1 This is supported by recently published results from an investigator-initiated clinical study conducted in China which reported that allogeneic MSCs cured or significantly improved functional outcomes in all seven treated patients with severe COVID-19 pneumonia.2

Additionally, in post-hoc analyses of a 60-patient randomized controlled study in chronic obstructive pulmonary disease (COPD), remestemcel-L infusions were well tolerated, significantly reduced inflammatory biomarkers, and significantly improved pulmonary function in those patients with elevated inflammatory biomarkers. Since the same inflammatory biomarkers are also elevated in COVID-19, these data suggest that remestemcel-L could be useful in the treatment of patients with ARDS due to COVID-19.The COPD study results have been submitted for presentation at an international conference, with full results to be submitted for publication shortly.

Remestemcel-L is being studied in numerous clinical trials across several inflammatory conditions, including in elderly patients with lung disease and adults and children with steroid-refractory acute graft versus host disease (aGVHD).3-5 This product candidate is currently being reviewed by the United States Food and Drug Administration (FDA) for potential approval in the treatment of children with steroid-refractory aGVHD.

Remestemcel-L Remestemcel-L is being developed for rare pediatric and adult inflammatory conditions. It is an investigational therapy comprising culture-expanded MSCs derived from the bone marrow of an unrelated donor and is administered in a series of intravenous infusions. Remestemcel-L is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in several diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

Intellectual PropertyMesoblasts intellectual property (IP) portfolio encompasses over 1,000 patents or patent applications in all major markets and includes the use of MSCs obtained from any source for patients with acute respiratory distress syndrome (ARDS),and for inflammatory lung disease due to coronavirus (COVID-19), influenza and other viruses. Additionally, these patents cover Mesoblasts manufacturing processes that yield industrial-scale cellular medicines.This IP position is expected to provide Mesoblast with substantial commercial advantages as it develops its product candidates for these conditions.

References1. Liu Y et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. Medrxiv 2020; https://doi.org/10.1101/2020.02.17.200241662. Leng Z, et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia[J]. Aging and Disease, 10.14336/AD.2020.02283. Kurtzberg J et al. Annual Meeting of the American Society for Transplantation Cell Therapy, 2020.4. Chaudhury S et al. A Phase 3 Single-Arm, Prospective Study of Remestemcel-L, Ex-Vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Steroid Refractory Acute GVHD in Pediatric Patients. Biol Blood Marrow Transplant 2018; 24:S119S290.5. Kurtzberg J et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant. 2014 Feb;20(2):229-35.

About MesoblastMesoblast Limited (Nasdaq: MESO; ASX: MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblasts proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast has filed a Biologics License Application to the United States Food and Drug Administration (FDA) to seek approval of its product candidate RYONCIL (remestemcel-L) for steroid-refractory acute graft versus host disease (acute GvHD). Remestemcel-L is also being developed for other rare diseases. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. If approved, RYONCIL is expected to be launched in the United States in 2020 for pediatric steroid-refractory acute GVHD. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking StatementsThis announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward- looking statements include, but are not limited to, statements about: the initiation, timing, progress and results of Mesoblasts preclinical and clinical studies, and Mesoblasts research and development programs; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblasts ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblasts product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblasts product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblasts ability to enter into and maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblasts expenses, future revenues, capital requirements and its needs for additional financing; Mesoblasts financial performance; developments relating to Mesoblasts competitors and industry; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

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Mesoblast To Evaluate Anti-Inflammatory Cell Therapy Remestemcel-L For Treatment Of COVID-19 Lung Disease - BioSpace

For Mr. Castillejo, the experience was surreal. He watched as millions of people reacted to the news of his cure and speculated about his identity. I was watching TV, and its, like, OK, theyre talking about me, he said. It was very strange, a very weird place to be. But he remained resolute in his decision to remain private until a few weeks ago.

For one, his doctors are more certain now that he is virus-free. We think this is a cure now, because its been another year and weve done a few more tests, said his virologist, Dr. Ravindra Gupta of the University of Cambridge.

Mr. Castillejo also tested his own readiness in small ways. He set up a separate email address and telephone number for his life as LP, as he refers to himself, and opened a Twitter account. He began talking weekly with Mr. Brown, the only other person who could truly understand what he had been through. In December, Mr. Castillejo prepared a statement to be read aloud by a producer on BBC Radio 4.

After talking through his decision with his doctors, friends and mother, he decided the time was right to tell his story.

I dont want people to think, Oh, youve been chosen, he said. No, it just happened. I was in the right place, probably at the right time, when it happened.

Mr. Castillejo grew up in Caracas, Venezuela. His father was of Spanish and Dutch descent which later turned out to be crucial and served as a pilot for an ecotourism company. Mr. Castillejo speaks reverently of his father, who died 20 years ago, and bears a strong resemblance to him. But his parents divorced when he was young, so he was primarily raised by his industrious mother, who now lives in London with him. She taught me to be the best I could be, no matter what, he said.

As a young man, Mr. Castillejo made his way first to Copenhagen and then to London in 2002. He was found to have H.I.V., the virus that causes AIDS, in 2003.

Read the rest here:
The London Patient, Cured of H.I.V., Reveals His Identity - The New York Times

Bone remodeling and regeneration are dependent on resident stem/progenitor cells with the capability to replenish mature osteoblasts and repair the skeleton.

Until now, it has been thought that stem cells for bone lie within the bone marrow and the outer surface of the bone. Many studies have described the existence of a network of vascular channels that helped distribute blood cells out of the bone marrow. However, none of the studies had proved the existence of cells within these channels.

A new study by the scientists from the UConn School of Dental Medicine has discovered the population of stem cells that reside along the vascular channels within the cortical bone and have the ability to generate new bone. These stem cells stretch across the bone and connect the inner and outer parts of the bone.

Lead investigator Dr. Ivo Kalajzic, professor of reconstructive sciences, said, This is a discovery of perivascular cells residing within the bone itself that can generate new bone-forming cells. These cells likely regulate bone formation or participate in bone mass maintenance and repair.

This is the first study that reports the existence of these progenitor cells within the cortical bone that can generate new bone-forming cellsosteoblaststhat can be used to help remodel a bone.

To reach this conclusion, the scientists observed the stem cells within an ex vivo bone transplantation model. These cells migrated out of the transplant and started to reconstruct the bone marrow cavity and form new bone.

However, further study is required to determine the cells potential to regulate bone formation and resorption.

The study is presented in the journal Stem Cells.

Read more:
These new stem cells have the ability to generate new bone - Tech Explorist

10 things to know about stem cell therapy

New Delhi, March 3 (IANSlife) The usage of stem cells to cure or treat a disease or repair the injured tissue is defined as stem cell therapy. The best example of the stem cell treatment is seen in patients suffering from restoring the vision of the damaged eyes, grafting of the skin in severe burnt conditions. Stem cell treatments for brain or neural diseases like Parkinson''s and Alzheimer''s disease, multiple sclerosis, preventing heart strokes, curing diabetes, kidney disorders, autism, and spinal cord injuries are progressively making their way. Vipul Jain, CEO of Advancells and also a Serial entrepreneur, explains in detail the treatment, its uses, cost and effectiveness.

Q: What are stem cells?

Undifferentiated cells that are able to differentiate and transform into any type of cells of the body when and where needed. They have an enormous potential to repair, heal and regenerate. Stem cells come from blood, bone marrow, umbilical cord blood and adipose tissue.

Types of stem cell therapy

Autologous stem cell therapy: Patient receives stem cells from his/her own body

Allogeneic stem cell therapy: Patient receives the stem cells donated by another individual

Autologous stem cell therapy is better than allogeneic stem cell therapy as chances of mismatching are not there and they pose the minimum risk of immune rejection. Also, no side effects or adverse effects are seen as a person''s own blood cells are used. They start the healing process immediately in a natural way.

What is stem cell therapy?

The usage of stem cells to cure or treat a disease or repair the injured tissue is defined as stem cell therapy. Stem cells can be obtained from the bone marrow, adipose tissues etc. Due to their tremendous potential to prevent and to treat various health conditions and to repair the injured tissues global research investigation is continuously being done as to explore the maximum advantage of these cell lines.

The best example of the stem cell treatment is seen in patients suffering from restoring the vision of the damaged eyes, grafting of the skin in severe burnt conditions. Stem cell treatments for brain or neural diseases like Parkinson''s and Alzheimer''s disease, multiple sclerosis, preventing heart strokes, curing diabetes, kidney disorders, autism, and spinal cord injuries are progressively making their way.

What are the sources of stem cell?

Depending upon the disease, different stem cell source can be used in a specific condition. The procedure may involve the extraction of stem cells from adipose tissue-derived stem cells with the combination of PRP (Platelet-rich plasma) or can be obtained from bone marrow that can differentiate into progenitor cells that differentiate into various other tissues which can help in the therapy.

Procedure of stem cell therapy

The stem cells are isolated from the bone marrow or adipose tissues followed by their processing and enrichment under sterile conditions. These activated stem cells are placed back into the patient''s body at the target site for repairing the damaged tissue. It is necessary that the stem cells are injected in the specific area of injury as only then the desired results will be achieved.

Adipose stem cells are preferred over bone marrow stem cells as they are easy to isolate and contain a higher number of stem cells.

Stem cells injection

The stem cells injections are gaining much interest because it is devoid of the painful procedure, takes less time in comparison to a surgery, there are no host and recipient rejections as stem cells are harvested from the patient''s body itself and a targeted delivery system is available.

The stem cells obtained are processed in a sophisticated stem cell lab and after activation are inserted back into the host with the help of intravenous, intramuscular, intra-arterial, intradermal and intrathecal injections as per the requirement of the treatment process.

What is the use of anesthetics and why? Usually, local anesthetics are used during a stem cell procedure to numb the area but sometimes general anesthesia is also given while extracting the stem cells from bone marrow. But it is necessary to find out what anesthetic your doctor uses during orthopedic stem cell treatments.

A number of anesthetics have been found to kill the stem cells thus; the treatment''s end result will greatly depend on the use of anesthetics. Some anesthetics very well sync with the stem cell and hence, aid in the treatment.

How good are the processing techniques in the onsite labs?

Stem cells are to be extracted and processed in a clean room, under aseptic conditions maintaining a controlled environment. The doctor should explain the entire process and the number of viable stem cells infused into the patient during the process. Also, the precision of the injections to provide good quality of stem cells at the site of injury will help in better and faster recovery of the patient''s damaged area.

Duration and cost of the therapy

Cost of the treatment and its duration varies from one patient to another. The disease which needs to be cured, the severity, age factor, health condition, etc, define the duration of the therapy. One may respond during the treatment phase itself while the other may show results after a few sessions or weeks. Depending upon the disease diagnosed, the stem cells extracted, duration of the therapy, other adjuvants used in the process, the cost of the stem cell therapy can vary.

Follow-up visits

It is essential that after the stem cell therapy the patient should visit the stem cell doctor for recuperation therapies. The primary goals of such therapy is the prevention of secondary complications, analysis of recovery of motor, sensory and all the bodily functioning, psychological support/counseling for depression, mood swings or anxiety etc. and reintegration into the community.

There can be different sets of precautions which need to be followed at various steps for the recovery of the damaged tissues. The treatment and post treatment conditions may vary from person to person depending upon the disease and the severity.

Success rate of stem cell therapy

Stem cell therapy has shown results in treating serious ailments like leukemia, grafting tissues, autism, orthopedic conditions and skin problems etc. Stem Cell Therapy has been successfully used in the treatment of around 80 serious disorders.

Survival rates among patients who received stem cell treatment are significantly high, whether the cell donors are related or unrelated to them. With the ongoing research around the world, scientists are exploring new possibilities in which a number of life threatening diseases can be prevented and cured hence, the stem cells have proved to be promising in the near future as many aspects are yet to be revealed.

--IANS

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Disclaimer :- This story has not been edited by Outlook staff and is auto-generated from news agency feeds. Source: IANS

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10 things to know about stem cell therapy - Outlook India

A new population of stem cells that can generate bone has been revealed by researchers, which they say could have implications in regenerative medicine.

A population of stem cells with the ability to generate new bone has been newly discovered by a group of researchers at the University of Connecticut (UConn) School of Dental Medicine, US.

The researchers present a new population of cells that reside along the vascular channels that stretch across the bone and connect the inner and outer parts of the bone.

This is a new discovery of perivascular cells residing within the bone itself that can generate new bone forming cells, said lead investigator Dr Ivo Kalajzic. These cells likely regulate bone formation or participate in bone mass maintenance and repair.

Stem cells for bone have long been thought to be present within bone marrow and the outer surface of bone, serving as reserve cells that constantly generate new bone or participate in bone repair. Recent studies have described the existence of a network of vascular channels that helped distribute blood cells out of the bone marrow, but no research has proved the existence of cells within these channels that have the ability to form new bones.

In this study, Kalajzic and his team are the first to report the existence of these progenitor cells within cortical bone that can generate new bone-forming cells osteoblasts that can be used to help remodel a bone.

To reach this conclusion, the researchers observed the stem cells within an ex vivo bone transplantation model. These cells migrated out of the transplant and began to reconstruct the marrow cavity and form new bone.

While this study shows there is a population of cells that can help aid formation, more research needs to be done to determine the cells potential to regulate bone formation and resorption, say the scientists.

According to the authors of the study: we have identified and characterised a novel stromal lineagerestricted osteoprogenitor that is associated with transcortical vessels of long bones. Functionally, we have demonstrated that this population can migrate out of cortical bone channels, expand and differentiate into osteoblasts, therefore serving as a source of progenitors contributing to new bone formation.

The results are published inSTEM CELLS.

The rest is here:
Stem cells that can grow new bone discovered by researchers - Drug Target Review

Stem cell research has been the subject of discussion and heated debate for many years. Much of the social and political drama surrounding stem cells is the result of misunderstanding what stem cells are, where they come from, and what they can do for those with injuries and diseases.

Working from a common set of facts is a great way to dispel controversy, however. Whether we fall into the pro-choice or pro-life camp, it is more than evident that supporting stem cell research, including the development of stem cell therapies, is very much a pro-life position to take.

Stem cells function essentially like raw materials for the body. Depending on instructions from the body (or researchers in laboratories), stem cells can become many other types of cells with specialized functions.

The daughters of stem cells either become new stem cells (self-renewal) or they become more specialized cells for use in specific areas of the body (differentiation). These specialized cells include brain cells, heart muscle cells, bone cells, blood cells and others.

There are several reasons why stem cells are the focus of some of the most important medical science research today:

This last avenue of medical research stem cell therapies is the most consequential as well as the most controversial, depending on your point of view. Understanding stem cell therapy and its divisiveness requires understanding where stem cells come from in medical research and why they have considerable palliative potential.

Stem cells come from one of these three sources:

Embryonic stem cells are the most controversial as well as the most important type of stem cells right now. Thanks to a low-information electorate and gross misinformation from within the government, embryonic stem cells remain mired in needless debate.

Despite the rhetoric, these cells arent harvested from slain newborns. Instead, they are carefully gathered from blastocysts. Blastocysts are three-to-five-day-old embryos comprised of around 150 cells. According to some religious-political arguments, blastocysts are potential human beings, and therefore deserve legal protection.

Embryonic stem cells are the most valuable in medical research because they are fully pluripotent, which means they are versatile enough to become any type of cell the body requires to heal or repair itself.

Adults have limited numbers of stem cells in a variety of bodily tissues, including fat and bone marrow. Unlike pluripotent embryonic stem cells, adult stem cells have more limits on the types of cells they can become.

However, medical researchers keep uncovering evidence that adult stem cells may be more pliable than they originally believed. There is reason to believe cells from adult bone marrow may eventually help patients overcome heart disease and neurological problems. However, adult stem cells are more likely than embryonic stem cells to show abnormalities and environment-induced damage, including cell replication errors and toxins.

The newest efforts in stem cell research involve using genetic manipulation to turn adult stem cells into more versatile embryonic variants. This could help side-step the thorny abortion controversy, but its also not clear at present whether these altered stem cells may bring unforeseen side-effects when used in humans.

More research is required to fully understand the medical potential of perinatal stem cells. However, some scientists believe they may in time become a viable replacement for other types of stem cells. Perinatal stem cells come from amniotic fluid and umbilical cord blood.

Using a standard amniocentesis, doctors can extract umbilical cord mesenchymal stem cells, hematopoietic stem cells, amniotic membrane and fluid stem cells, amniotic epithelial cells and others.

Among other things, stem cell therapy is the next step forward for organ transplants. Instead of waiting on a transplant waiting list, patients may soon be able to have new organs grown from their very own stem cells.

Bone marrow transplants are one of the best-known examples of stem cell therapy. This is where doctors take bone marrow cells and induce them to become heart muscle cells.

Stem cell-based therapies hold significant promise across a wide range of medical conditions and diseases. With the right approach, stem cells show the potential to:

As the FDA notes, there is a lot of hype surrounding stem cell therapy. Much of it is warranted, but some of it deserves caution.

According to the FDA, stem cells have the potential to treat diseases or conditions for which few treatments exist. The FDA has a thorough investigational process for new stem cell-based treatments. This includes Investigational New Drug Applications (IND) and conducting animal testing.

However, the FDA notes that not every medical entity submits an IND when they bring a new stem cell therapy to market. It is vital that patients seek out only FDA-reviewed stem cell therapies and learn all they can about the potential risks, which include reactions at the administration site and even the growth of tumors.

The FDA submitted a paper, Clarifying Stem-Cell Therapys Benefits and Risks, to the New England Journal of Medicine in 2017. Its goal is to help patients fully understand what theyre getting themselves into.

For now, a great deal more research is required before we begin deploying stem cell therapies on a larger scale. The only FDA-approved stem cell therapies on the market today involve treating cancer in bone marrow and blood. Some clinics claim their therapy delivers miracle-like cures for everything from sports injuries to muscular dystrophy, but there just isnt enough evidence yet to take them at face value.

Unfortunately, the religious and political climate makes this evidence difficult to achieve. In some parts of the United States, the hostility toward stem cell researchers and medical practitioners has reached dangerous new levels.

Republicans in Ohio and Georgia want to make it illegal for doctors to perform routine procedures on ectopic pregnancies. This condition is life-threatening for the mother and involves the removal of a nonviable embryo from the fallopian tube.

These laws wouldnt just outlaw ectopic pregnancy surgery in the name of potential human life. It would, in fact, require women to undergo a reimplantation procedure after the ectopic pregnancy is corrected by a physician. If this procedure was actually medically possible, it would be dangerous and unnecessary. Thankfully, it doesnt exist outside the nightmarish imaginations of some of the more extreme Christian lawmakers and Planned Parenthood demonstrators.

Acquiring embryonic stem cells from ectopic pregnancies would seem to be the least controversial way to go about it. Unfortunately, even that small step toward medical progress sees itself hampered by reactionary politics.

No matter how theyre acquired, however, the 150 or so cells in blastocysts are packed with medical potential. Its clear that further exploration down this road will unlock unprecedented scientific progress. It will also, almost certainly, save many times more potential life than even the most outlandish estimates of what the achievement will cost us to achieve. Abortions today are rarer and safer than ever, and the vast majority occur within eight weeks of conception.

The medical community is poised for a revolution here, using these and other nonviable embryos and blastocysts. But realizing that potential requires, among other things, that we collectively make peace with modern medicine and family planning.

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Despite Pro-Life Claims, Stem Cell Therapy Has Very Real Benefits and Should Be Accessible - Patheos

Steven Hodi Jr., the i3 Centers other PI, and director of Melanoma Center and the Center for Immuno-Oncology at Dana-Farber, and professor of medicine at Harvard Medical School (HMS), is leading the clinical cancer vaccine trial. He has been at the forefront of developing cancer immunotherapies using immune checkpoint inhibitors, a class of drugs able to re-activate tumor-destroying T cells that are muted in the tumor microenvironment. The funding for this center provides a unique opportunity to unite key investigators for translating fundamental advancements in immunology and biomedical engineering into highly synergistic approaches to improve the treatments for cancer patients, said Hod

Using both in vivo and ex vivo biomaterials-based approaches, the i3 Center aims to boost tumor-specific activities of cytotoxic T cells, by boosting different stages of the normal process by which T cells develop, and acquire anti-cancer activity. T cells normal development starts in the bone marrow where hematopoietic stem cells generate T cell progenitor cells. These migrate to the thymus to differentiate into nave T cells, which then travel further to lymph nodes. There, they encounter cancer-derived antigens presented to them by specialized antigen-presenting cells (APCs) that can activate T cells to recognize and eliminate cancer cells.

In relation to adoptive T cell therapies in which T cells are given to patients to fight their cancers, one team at the i3 Center will be led by Dana-Farber researchers Catherine J. Wu and Jerome Ritz, who along with Mooney, will develop and test biomaterials that can better mimic normal APCs in activating and directing the function of patient-derived T cells outside the human body, prior to their transplantation. Wu is chief of the Division of Stem Cell Transplantation and Cellular Therapies, and Ritz is executive director of the Connell and OReilly Families Cell Manipulation Core Facility at Dana-Farber.

We need to make efforts to enhance the ability of theimmune systemto recognizetumor cells. One directionmylaboratoryis taking makes use of innovative biomaterialsto help us to efficiently expandpolyclonaltumor-specificfunctionally-effectiveT cellsex vivoin a way that can be readily translated to theclinical setting. In our studies, we are currently focusing on melanoma and acute myeloid leukemia, said Wu, whose research interests include understanding the basis of effective human anti-tumor responses, including the identification and targeting of the tumor-specific antigens.

A second project explores the use of DNA origami, biocompatible nanostructures composed of DNA, to create cancer vaccines. DNA origami could provide significant advantages in presenting tumor-specific antigens and immune-enhancing adjuvants to APCs because the concentrations, ratios, and geometries of all components can be modulated with nano-scale precision to determine configurations that are more effective than other vaccination strategies. The project will be run by Wyss Institute Core Faculty member William Shih, Derin Keskin, lead immunologist at Dana-Farbers Translational Immunogenomics Lab, and Mooney.

In a third project, David Scadden, professor at Harvards Department of Stem Cell and Regenerative Biology, will collaborate with Mooney to build on their previous work. They will engineer biomaterials that recreate key features of the normal hematopoietic stem cell niche in the bone marrow. Such implantable biomaterials could help rapidly amplify T cell progenitor cells, and enhance T cell-mediated anti-cancer immunity. Scadden also is the Gerald and Darlene Jordan Professor of Medicine at Harvard University, and co-director of the Harvard Stem Cell Institute.

The i3 Centers investigators anticipate that it will stimulate additional cross-disciplinary concepts and research, due to the culture of continuous interactions, sharing of findings, data and samples between all investigators, as well strong biostatistical expertise provided by Donna Neuberg, a senior biostatistician broadly involved with exploring immune-modulating cancer interventions at the Dana-Farber.

This new i3 Center for cancer immunotherapy innovation really embodies how the Wyss Institute with its unparalleled capabilities in bioengineering and serving as a site for multidisciplinary collaboration, and can liaise with clinicians and researchers at our collaborating institutions to confront major medical problems and bring about transformative change, said Wyss Founding Director Donald Ingber. He is also theJudah Folkman Professor of Vascular Biologyat HMS and the Vascular Biology Program at Boston Childrens Hospital, and Professor of Bioengineering at SEAS.

Continued here:
NIH-funded i3 Center formed to advance cancer immunotherapy - Harvard Gazette

Researchers from UConn School of Dental Medicine have recently discovered a group of stem cells that help in generating a new bone. In regards with this, Dr Ivo Kalajzic, professor of reconstructive sciences, stated that, this newly discovered perivascular stem cells that reside in the bone itself have capability of generating the bone and these cells are highly instrumental in repair & mass maintenance of the bone along with its formation.

Since ages, it has been thought that stem cells only reside in bone marrow and exterior surface of the bone stores the cells that continuously generate new bone or repair the bone. Postdoctoral individuals Dr Sierra Root and Dr Natalie Wee, and collaborators at Harvard, Maine Medical Research Center, and the University of Auckland also were part of this study along with Dr Ivo Kalajzic and confirmed that these new cluster of cells residing in the vascular channels that range across the bone and serve as connection between inner and outer part of the bone is capable of generating a new bone.

This team is also pioneer in bringing forward a study that says existence of these progenitor cells inside cortical bone not only generates a new bone but also help remodeling of the bone. The conclusion was made after these researchers observed that these stem cells within an ex vivo bone transportation model migrated out of the transplant and started manufacturing a new bone marrow cavity along with completely new bone.

In order to establish this, more research needs to done as it will definitely turn out wonderful to the field of medical science and mankind.

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Stem Cells that will aid new bone generation discovered as per latest research - Medical Herald

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Two-year-old Regann Moore lights up as she watches videos on her iPad at home on Thursday, Feb. 20, 2020. Moore has a rare disease known as Krabbe Disease and received a life-saving stem cell donation less than a month after being born.(Photo: Nathan Papes/Springfield News-Leader)

Soon after the News-Leader published a story about 2-year-old Regann Moore,a Springfield child whose life was saved thanks to a newborn screening test, someone tweeted the story toMissouri State Rep. Becky Ruth.

"I bawled my eyes out," Ruth said. "I just cried."

She cried because she knew Regann is alive thanks to the death of Ruth's grandson, Brady.

"I cry and smile when I see these children," Ruth said. "We are always so thankful. For us, we see Brady's death wasn't in vain. His legacy lives on by helping save the lives of other children."

More: Springfield child with rare, deadly disease continues to amaze doctors, family

Regann, who is 2 now, was diagnosed right after she was born withKrabbe Disease, a rare metabolic disorder that must be diagnosed at birth and treated as soon as possible with a stem cell donation.

The newborn screening is important because babies with Krabbe Disease appear healthy at birth. Signs something is wrong usually don't appear until it's too late for treatment to be effective.

That is what happened to Brady in 2009. He wasn't diagnosed with the disease until he was 4.5 months old too late for treatment.

Brady died 10 days before his first birthday.

Brady Cunningham died of Krabbe Disease just before his first birthday.(Photo: Courtesy of the Cunningham family)

That's why Ruth and her family fought to get lawmakers on board with making sure all newborns in Missouri are screened for Krabbe Disease.

TheBrady Alan Cunningham Newborn Screening Act was passed in 2009 and screening began in 2012. Ruthsaid her family was OK with the three-year lag because they realized the lab needed time to become equipped to test for the disease.

Missouri is one of just a few states that do the newborn screening.

Brady's law also includes screening for Pompe, Fabry, Gauche and Niemann-Pick diseases. Since then, SCID, MPS I, MPS II and SMA diseases are screened, as well.

Ruth became a state representative in 2015and said newborn screening is her passion.

Her experience with getting Brady's law passed is what led her to seek office.

"It showed me what just a regular everyday person can do and what a differenceyou can make," Ruth said. "People a lot of times complain about politicians and the legislature, but we also do very good things here."

Ruth said her family knows of another child with Krabbe Disease who was saved thanks to newborn screening and a stem cell transplant.

That child is now 4. Ruth said her family and that child's family have a "strong connection."Ruth said shehopes to someday meet Regann's family.

Brady Cunningham was born in 2008. His family is from Campbell in southeast Missouri.

Bradyappeared healthy at birth and was not tested for Krabbe Disease.

Ruth said he started having health problems after about a month and a half. Brady went through "a myriad of diagnoses," Ruth recalled, including acid reflux and seizures.

"Finally my daughter took him to Children's Hospital in St. Louis," she said. "They promised her he wouldn't leave without a diagnosis."

Missouri State Rep. Becky Ruth was moved to tears after reading about Regann Moore, a Springfield child whose life was saved thanks to newborn screening for Krabbe Disease. Ruth and her family encouraged Missouri lawmakers to make sure all Missouri babies are tested for the deadly disease after her grandson, Brady, died from it.(Photo: Submitted by Becky Ruth)

Three weeks later, Brady was diagnosed with Krabbe Disease, which rapidly destroys the nervous system.

"We were told there was nothing they could do," she said. "It was one of the worst days of all of our lives."

Brady was 4.5 months old when he was diagnosed. In order for a stem cell donation to have any chance of being effective, babies must have the transplant within the first month of their life.

Regann, the Springfield child, was given a stem cell donation thanks to an umbilical cord donation.

Thediseaseaffects about one in every 100,000 people in the United States.

"They are missing an enzyme that helps keep their nervous system intact," said Dr. Shalini Shenoy, Regann's transplant doctor. "Because this is missing, they have degeneration of the brain and nervous system. And if you let it progress, it is fatal very early."

Without the stem cell donation, babies die within the first few months, Shenoy said.

"You can't change someone's genetic makeup," Shenoy said. "But when you put stem cells into their bone marrow from somebody else who is normal, some of these cells migrate into their brain and into their nervous system and supply what they are lacking themselves."

It takes some time for the transplant to begin working for the transplanted cells to "settle down" and begin making the missing enzyme, Shenoy said.

"Because of that, the earlier you transplant a Krabbe patient, the more you will be able to rescue them," she said. "You want to catch them before too much damage is done. Once there's a lot of nerve damage, it's not reversible. If I saw a Krabbe patient two months after they were born or four months after they were born when they already had major problems, it's unlikely I'd be able to rescue them too much."

Since the screening and the stem cell transplant treatment are both relatively recent medical advancements, Shenoy said it's anybody's guess what the future will hold for children who, like Regann, were successfully treated with a stem cell transplant early on.

Ferrell Moore holds his two-year-old daughter Regann Moore at their home on Thursday, Feb. 20, 2020. Regann has a rare disease known as Krabbe Disease and received a life-saving stem cell donation less than a month after being born.(Photo: Nathan Papes/Springfield News-Leader)

Regann can't stand on her own or walk yet. But her family is determined to make that happen. She cannot talk but is learning sign language to communicate.

She has regular visits with speech and occupational therapists.

Regann's dad Ferrell Moore got to take her to the circus recently, something the little girl seemed to enjoy.

"She is the joy of my life," Ferrell Moore said. "When I come home, it couldn't be any better to see her and how happy she is to see me."

Read or Share this story: https://www.news-leader.com/story/news/local/ozarks/2020/03/05/grandma-who-helped-pass-newborn-screening-law-tells-story-bill/4954655002/

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'His legacy lives on': Grandmother who helped create newborn screening law tells history of bill - News-Leader

The Global Stem Cells Market is expected to grow from USD 115.46 Million in 2018 to USD 325.84 Million by the end of 2025 at a Compound Annual Growth Rate (CAGR) of 15.97%.

The Stem Cells Market research presents a study by combining primary as well as secondary research. The report gives insights on the key factors concerned with generating and limiting Stem Cells market growth.

Additionally, the report also studies competitive developments, such as mergers and acquisitions, new partnerships, new contracts, and new product developments in the global Stem Cells market. The past trends and future prospects included in this report makes it highly comprehensible for the analysis of the market. Moreover, the latest trends, product portfolio, demographics, geographical segmentation, and regulatory framework of the Stem Cells market have also been included in the study.

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Stem Cells Market Segment by Manufacturers includes: The report deeply explores the recent significant developments by the leading vendors and innovation profiles in the Global Stem Cells Market including are Anterogen Co., Ltd., Holostem Terapie Avanzate Srl, Medipost Co., Ltd., Osiris Therapeutics, Inc., Pharmicell Co., Ltd., Allosource, JCR Pharmaceuticals Co., Ltd., Nuvasive, Inc., and RTI Surgical, Inc.. On the basis of Cell Source, the Global Stem Cells Market is studied across Adipose Tissue-Derived Mesenchymal Stem Cells, Bone Marrow-Derived Mesenchymal Stem Cells, and Cord Blood/Embryonic Stem Cells.On the basis of Type, the Global Stem Cells Market is studied across Allogeneic Stem Cell Therapy and Autologous.On the basis of Therapeutic Application , the Global Stem Cells Market is studied across Cardiovascular Diseases, Gastrointestinal Diseases, Musculoskeletal Disorders, Surgeries, and Wounds and Injuries.

Global Stem Cells market report covers all the major participants and the retailers will be in conscious of the development factors, market barriers & threats, and the opportunities that the market will offer in the near future. The report also features the historical revenue of the market; industry trends, market volume, and consumption in order to gain perceptions about the political and technical environment of the Stem Cells market share.

This report focuses on the Stem Cells in Global market, especially in

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The report gives detailed analysis in terms of qualitative and quantitative data pertaining to the projected potential opportunities that influence markets growth for the forecast period. With a major focus on the key elements and segments of the global Stem Cells market that might affect the growth prospects of the market, making it a highly informative document.

Major Points covered in this Report:

Market Segmentation:

Regional market analysis

The content of the study subjects includes a total of 15 chapters:

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Originally posted here:
Stem Cells Market Top Impacting Factors to Growth of the Industry by 2025 - Bandera County Courier

The success of approved stem cell therapies has caused a surge in interest of biopharma developers in this field; many innovator companies are currently progressing proprietary leads across different phases of clinical development, with cautious optimism

LONDON, March 4, 2020 /PRNewswire/ -- Roots Analysishas announced the addition of "Global Stem Cells Market: Focus on Clinical Therapies, 20202030 (Based on Source (Allogeneic, Autologous); Origin (Adult, Embryonic); Type (Hematopoietic, Mesenchymal, Progenitor); Lineage (Amniotic Fluid, Adipose Tissue, Bone Marrow, Cardiosphere, Chondrocytes, Corneal Tissue, Cord Blood, Dental Pulp, Neural Tissue Placenta, Peripheral Blood, Stromal Cells); and Potency (Multipotent, Pluripotent))" report to its list of offerings.

There is a growing body of evidence supporting the vast applicability and superiority of treatment outcomes of stem cell therapies, compared to conventional treatment options. In fact, the unmet needs within this domain have spurred the establishment of many start-ups in recent years.

To order this 500+ page report, which features 185+ figures and 220+ tables, please visit this link

Key Market Insights

Over 280 stem cell therapies are under development, most of which are allogeneic products

More than 50% of the pipeline candidates are in the mid to late phase trials (phase II and above), and allogenic therapies (majority of which are derived from the bone marrow) make up 65% of the pipeline.

70% of pipeline candidates are based on mesenchymal stem cells

It is worth highlighting that the abovementioned therapies are designed to treat musculoskeletal (22%), neurological (21%) and cardiovascular (15%) disorders. On the other hand, hematopoietic stem cell-based products are mostly being evaluated for the treatment of oncological disorders, primarily hematological malignancies.

Close to 85% stem cell therapy developers are based in North America and Asia-Pacific regions

Within these regions, the US, China, South Korea and Japan, have emerged as key R&D hubs for stem cell therapies. It is worth noting that majority of the initiatives in this domain are driven by small / mid-sized companies

Over 1,500 grants were awarded for stem cell research, since 2015

More than 45% of the total amount was awarded under the R01 mechanism (which supports research projects). The NCI, NHLBI, NICHD, NIDDK, NIGMS and OD emerged as key organizations that have offered financial support for time periods exceeding 25 years as well.

Outsourcing has become indispensable to R&D and manufacturing activity in this domain

Presently, more than 80 industry / non-industry players, based in different regions across the globe, claim to provide contract development and manufacturing services to cater to the unmet needs of therapy developers. Examples include (in alphabetical order) Bio Elpida, Cell and Gene Therapy Catapult, Cell Tech Pharmed, GenCure, KBI Biopharma, Lonza, MEDINET, Nikon CeLL innovation, Roslin Cell Therapies, WuXi Advanced Therapies and YposKesi.

North America and Asia-Pacific markets are anticipated to capture over 80% share by 2030

The stem cell therapies market is anticipated to witness an annualized growth rate of over 30% during the next decade. Interestingly, the market in China / broader Asia-Pacific region is anticipated to grow at a relatively faster rate.

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Key Questions Answered

The USD 8.5 billion (by 2030) financial opportunity within the stem cell therapies market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom stem cell therapies are currently considered to be a promising alternatives for the treatment of a myriad of disease indications, with the potential to overcome challenges associated with conventional treatment options. The report includes detailed transcripts of discussions held with the following experts:

The research covers brief profiles of several companies (including those listed below); each profile features an overview of the company, financial information (if available), stem cell therapy portfolio and an informed future outlook.

For additional details, please visit

https://www.rootsanalysis.com/reports/view_document/stem-cells-market/296.html email sales@rootsanalysis.com

You may also be interested in the following titles:

Contact:Gaurav Chaudhary+1(415)800-3415+44(122)391-1091Gaurav.Chaudhary@rootsanalysis.com

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With Over 280 Therapies Under Evaluation, the Stem Cell Therapy Market is Estimated to be Worth USD 8.5 Billion by 2030, Claims Roots Analysis - P&T...

Graft-versus-host disease can occur any time after a transplant when donor bone marrow or stem cells attack the recipient

CytoDyn Inc (), a late-stage biotechnology company, said Wednesday that it has treated its first patient with its lead drug leronlimab (PRO 140), in its Phase 2 clinical trial for graft-versus-host disease (GvHD) under the modified trial protocol.

Graft-versus-host disease can occur at any time after a transplant. It is a rare condition that typically occurs when donor bone marrow or stem cells attack the recipient.

In a statement, the Vancouver, Washington-based company said the modified protocol now includes reduced intensity conditioning (RIC) patients and an open-label design under which all enrollees receive leronlimab. The modified protocol also provides for a 50% increase in the dose of leronlimab to more closely mimic preclinical dosing.

The next review of data by the independent data monitoring committee (IDMC) will occur after the enrollment of 10 patients under the amended protocol after each patient has been dosed for 30 days, said the company.

CytoDyn CEO Nader Pourhassan pointed out that GvHD is a life-threatening complication following bone marrow transplantation in patients with leukemia, who have compromised immune systems due to treatment with aggressive cancer therapies.

We selected GvHD as one of our immunology indications for leronlimab, as it targets and masks the CCR5 receptor on T cells. This receptor on T cells is an important mediator of inflammatory diseases including GvHD, especially in organ damage that is the most frequent cause of death in these patients, said Dr Pourhassan.

Based upon the compelling results in our preclinical studies, we are optimistic about the opportunities for leronlimab to provide a therapy for transplant patients to mitigate GvHD, he added.

A preclinical study by Dr Denis R Burger, CytoDyns former chief science officer, and Daniel Lindner, from the Department of Translational Hematology and Oncology Research, at The Cleveland Clinic, was published in the peer-reviewed journal called the Biology of Blood and Marrow Transplantation.

The US Food and Drug Administration earlier granted orphan drug designation to leronlimab for the prevention of GvHD. The designation provides CytoDyn with various incentives and benefits including seven years of US market exclusivity for leronlimab in GvHD, subject to FDA approval for use in this indication.

Leronlimab was earlier granted Fast Track status by the FDA for the treatment of HIV in combination with the cocktail known as highly active antiretroviral therapy (HAART), and for metastatic triple-negative breast cancer, a rare variety which doesnt respond to some treatments.

Leronlimab has completed nine clinical trials and has been given to 800 patients in HIV treatment programs, without a single drug-related serious adverse event. CytoDyn is developing leronlimab to battle multiple diseases. The company has also filed an IND application and a Phase 2 clinical trial protocol with the FDA to treat patients with NASH - damage caused by a build-up of fat in the liver.

Contact the author Uttara Choudhury at[emailprotected]

Follow her onTwitter:@UttaraProactive

Continued here:
CytoDyn treats first patient with leronlimab in Phase 2 trial for GvHD under modified protocol - Proactive Investors USA & Canada

INTRODUCTION

In recent years, organoids have emerged as powerful tools for basic research, drug screening, and tissue engineering. The organoids formed in vitro show many features of the structural organization and the functional hallmarks of adult or embryonic anatomical structures (1). In addition, the formation of organoids alleviates the need to perform animal studies and provides an attractive platform for robust quantitative studies on the mechanisms regulating organ homeostasis and tissue repair in vivo (1). The formation of organoids usually starts with populations of stem cells. They are therefore expected to be heterogeneous because pluripotent stem cells [induced pluripotent stem cells (pscs) or embryonic stem cells] have been shown to dynamically and stochastically fluctuate from ground to differentiated state (2). In the same vein, LGR5+ intestinal stem cells are reported to contain several distinct populations (3). As such, the formation of organoids involves the inherent capacity of these heterogeneous populations to self-sort and self-pattern to form an organized three-dimensional (3D) architecture (4). However, the rules underlying organoid formation as well as the contribution of intrinsic population heterogeneity to the organoid self-assembly remain poorly understood (5). Consequently, there is a need for novel quantitative approaches at the single-cell level to reliably understand the mechanisms of spatial tissue patterning in 3D organoids, for which microfluidic and quantitative image analysis methods are well suited.

In this work, we use mesenchymal progenitors, alternatively named mesenchymal stromal cells (MSCs), which constitute a self-renewing population with the ability to differentiate into adipocytes, chondrocytes, and osteoblasts (5). Although human MSCs (HMSCs) express high levels of undifferentiation markers (e.g., CD105, CD44, CD73), they constitute a heterogeneous population of cells that exhibit considerable variation in their biophysical properties and epigenetic status, as well as the basal level of expression of genes related to differentiation, immunoregulation, and angiogenesis (6, 7). Nonetheless, their aggregation leads to the formation of highly cohesive 3D spherical structures [which we designate hereafter as mesenchymal bodies (MBs)] with improved biological activities in comparison to 2D cultures (8). However, little is known on how HMSCs self-organize or whether the intrinsic heterogeneity of the population regulates MB formation and individual cell functions in 3D.

The self-aggregation of HMSCs into MBs can recapitulate the early stages of mesenchymal condensation, and it promotes the secretion of paracrine molecules taking part in the process of ossification (9). During mesenchymal condensation in vivo, mesenchymal progenitors self-aggregate and form dense cell-cell contacts that lead to the initiation of bone organogenesis through endochondral (necessitating a chondrogenic intermediate) and intramembranous (direct osteogenic differentiation) ossification (10). In addition, the formation of these 3D MBs in vivo is associated with the secretion of important paracrine molecules such as prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF), which participate in the recruitment of endogenous osteoblasts, osteoclasts, and blood vessels, leading to the initiation/restoration of bone homeostasis (11, 12). In these two ossification processes, the induction of nuclear factor B (NF-B) target genes, such as cyclooxygenase-2 (COX-2), and their downstream products (e.g., PGE2 and VEGF) plays a critical role as developmental regulators of ossification and bone healing (13). However, while mesenchymal condensation is critical for bone organogenesis, there is still a limited understanding on how the cellular spatial organization within 3D MBs regulates the individual cells endocrine functions (14).

In the present work, we interrogate the influence of phenotypic heterogeneity within a population of stem cells on the mechanisms of self-assembly and functional patterning within 3D organoids using HMSCs as a model of heterogeneous progenitor cell population. This is performed using a novel microfluidic platform for high-density formation of mensenchymal bodies, combined with the analysis of individual cells by quantitative image analysis. Our study reveals that the progenitor cell population self-assembles in a developmentally hierarchical manner. We also find that the structural arrangement in mensenchymal bodies is linked with the functional patterning in 3D, through a modulation of the activity of regulatory molecular signaling at a local scale. This study demonstrates the interplay between cell size and differentiation status, which mediates cellular spatial rearrangement in 3D, leading to the regionalized activation of unique biological functions while forming aggregates.

HMSCs are known to constitute a heterogeneous population (6, 7). In this study, fetal HMSCs were derived from the Whartons jelly of the umbilical cord (UC). UC-derived HMSCs are considered to be more primitive than HMSCs derived from adult bone marrow because of their higher proliferative capacity, their ability to form colony-forming unitfibroblast, as well as their lower degree of basal commitment (15). To examine the cellular diversity within the population, HMSCs were first characterized by their expression of membrane markers. Most of the HMSC population consistently expresses CD73, CD90, CD105, and CD146, but not CD31 (an endothelial cell marker), CD34 (a hematopoietic cell marker), CD14 (an immune cell marker), or human leukocyte antigenDR (HLA-DR) (a type of major histocompatibility complex II) (Fig. 1, A to F, and fig. S1, A to C). However, a deeper analysis of the flow cytometric data shows that the HMSC population contains cells of heterogeneous size [coefficient of variation (CV) = 33 to 37%] (Fig. 1, G and I), having a broad distribution in the expression of CD146 (Fig. 1F). Of note, the CD146 level of expression was linked to the size of the cells: The highest levels of CD146 were found for the largest cells (Fig. 1, H and J). Similar correlations with cell size were also observed for CD73, CD90, and CD105 (fig. S1, D to F). In addition, upon specific induction, the HMSC population used in this study successfully adopted an adipogenic (Fig. 1K), an osteogenic (Fig. 1L), or a chondrogenic (Fig. 1M) phenotype, demonstrating their mesenchymal progenitor identity.

(A) Percentage of positive cells for CD31, CD73, CD90, CD105, and CD146 (n = 3). Representative histograms of the distribution of the CD31 (B), CD73 (C), CD90 (D), CD105 (E), and CD146 (F) level of expression are shown. (G) Representative histogram of the forward scatter (FSC) distribution. (H) Correlation between cell size [FSC and side scatter (SSC)] and the level of CD146 expression. (I) Representative histogram of the cell projected area distribution. (J) Representative histogram of the size distribution of the CD146dim, CD146int, and CD146bright (ImageSteam analysis). (K) Representative images of hMSCs differentiated toward adipogenic lineage (Oil Red O staining). (L) Representative images of UC-hMSCs differentiated toward osteogenic lineage in (Alizarin Red S staining). (M) Representative images of UC-hMSCs differentiated toward chondrogenic lineage (Alcian Blue staining in 2D and cryosectioned micromass cultures). Scale bars, 50 m. The images were acquired using a binocular. FITC-A, fluorescein isothiocyanateA; APC-A, allophycocyanin-A.

To interrogate contribution of cellular heterogeneity (i.e., in terms of size and levels of CD marker expression) in the self-organization of HMSCs in 3D, MBs were formed at high density on an integrated microfluidic chip. This was done by encapsulating cells into microfluidic droplets at a density of 380 cells per droplet, with a CV of 24% (fig. S2, A and B). The drops were then immobilized in 250 capillary anchors in a culture chamber, as previously described (Fig. 2, A and B) (16). The loading time for the microfluidic device was about 5 min, after which the typical time for complete formation of MBs was about 4 hours (movie S1), as obtained by measuring the time evolution of the projected area (Fig. 2, C and D) and circularity of individual MBs (Fig. 2E and movie S2). The protocol resulted in the formation of a single MB per anchor (fig. S2C) with an average diameter of 158 m (Fig. 2F), when starting with a seeding concentration of 6 106 cells ml1. The diameter of the aggregates can easily be tuned by modulating the concentration of cells in the seeding solution (fig. S2, A and B). In addition, the complete protocol yielded the reproducible formation of a high-density array of fully viable MBs ready for long-term culture (for the images of the individual fluorescent channel, see Fig. 2G and fig. S2D), as described previously (16). Of interest, the CV of the MB diameter distribution was lower than the CV of the individual cell size and of the cell number in droplets (CV MB diameter = 13.3%, CV cell number per drop = 24%, and CV cell size = 35%), which demonstrates that the production of MBs leads to more homogeneous size conditions, compared with the broad heterogeneity in the cell population.

(A) Chip design. Scale bar, 1 cm. (B) Schematized side view of an anchor through the MB formation and culture protocol. (C) Representative time lapse of an MB formation. Scale bar, 100 m. (D and E) Measurement of the time evolution of the projected area (D) and circularity of each aggregate (E). n = 120 MBs. (F) Distribution of the MB diameter normalized by the mean of each chip (n = 10,072 MBs). (G) Top: Representative images of MBs after agarose gelation and oil-to-medium phase change. Bottom: The same MBs are stained with LIVE/DEAD. Scale bar, 100 m. (H) Representative images of MBs formed in the presence of EDTA, an N-cadherin, or a CD146-conjugated blocking antibody (Ab) (the red color shows the position of the CD146 brightest cells, and the dilution of the antibody was 1/100 and remain in the droplet for the whole experiment). Scale bar, 100 m. The images were acquired using a wide-field microscope.

To gain insight into the cellular components required to initiate the self-organization of HMSCs in 3D, the MB formation was disrupted by altering cell-cell interactions. This was first performed by adding EDTA, a chelating agent of the calcium involved in the formation of cadherin junctions, to the droplet contents. Doing so disrupted the MB formation, as shown in Fig. 2H, where the projected area of the cells increased and the circularity decreased in the presence of EDTA compared with the controls, as previously reported (17). The role of N-cadherins among different types of cadherins was further specified by adding a blocking antibody in the droplets before MB formation. This also led to a disruption of the MB formation, demonstrating that N-cadherin homodimeric interactions are mandatory to initiate the process of HMSC aggregation. CD146 [melanoma cell adhesion molecule (M-CAM)] plays important dual roles: as an adhesion molecule (that binds to Laminin 411) (18) and a marker of the commitment of HMSCs (19). We, thus, interrogate its contribution to MB formation. The addition of a CD146-conjugated blocking antibody also disrupted the formation of the MB (Fig. 2H), demonstrating that cell-cell interactions involving CD146 are also required during MB formation, as reported with other cell types (18). Of note, the brightest signal from the CD146-stained cells was located in the core of the cellular aggregates (Fig. 2H), suggesting that HMSCs self-organize relatively to their degree of commitment.

We found that the population of HMSCs constituted of cells of broad size and expressing different levels of undifferentiated markers [i.e., CD90, CD73, CD105, and CD146 are known to be down-regulated upon differentiation; (20)] and that the cells are capable of self-organizing cohesively in 3D. To better understand how the heterogeneous cells organized within the MBs, we measured how the different cell types composing the population self-assembled spatially in 3D by investigating the role of CD146. For this purpose, the CD146dim and CD146bright cells were separated from the whole HMSC population by flow cytometry (Fig. 3, A and B). The cells were then reseeded on a chip for the MB formation after fluorescently labeling the brighter and/or the dimmer CD146 populations. Image analysis revealed that the CD146bright cells were mostly located in the center of the cellular aggregates, while CD146dim cells were found at the boundaries of the MBs (Fig. 3, C to E, figs. S3A and S5A for confocal images, and movie S1). This organization was stable for a 3-day culture (fig. S3B).

(A) Representative dot plot of the hMSC population separation based on the level of CD146: The CD146dim constitutes 20% of the population expressing the highest levels of CD146; the CD146bright constitutes the 20% of the population expressing the lowest levels of CD146. (B) Fluorescence signal distribution in the CD146dim and CD146bright populations after cell sorting. (C) After cell sorting, the CD146bright or the CD146dim was stained with Vybrant Dil (red) or Vybrant DiO (green), remixed together and allowed to form MBs. Representative images of the CD146bright and CD146dim within the MBs. Scale bar, 100 m (n = 185 MBs). (D) The position of the CD146bright and CD146dim was quantified by correlating the fluorescence signal of the different stained cells as a function of their radial position within the MBs, after the staining of individual population with Vybrant Dil (CD146bright) = 500 and CD146dim (MBs; CD146bright = 85). Error bars show the SD. (E) Schematized representation of the structural organization of MBs. (F and G) RT-qPCR analysis of the relative RUNX-2, CEBP/, and SOX-9 expression to glyceraldehyde-3-phosphate dehydrogenase (GADPH) [Ct (cycle threshold) (D) and relative RNA expression (E)] in the CD146bright and CD146dim populations (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001.

As we found that the CD146bright cells were larger than the CD146dim cells, the cells from the HMSC population were also separated on the basis of their relative size (a parameter that also discriminates the CD90, CD105, and CD73bright from the CD90, CD105, and CD73dim cells; fig. S1, D to F). After reseeding on the chip, the MBs were composed of large cells in the core, while the smallest cells were located at the boundaries, as expected from the previous experiments (fig. S3A). Moreover, we found that the speed of self-assembly of each population is not related to the rearrangement of CD146dim and CD146bright cells in 3D, because the mixing of dissociated cells or the fusion of aggregates made each population give rise to the same structural organization (21). It is well established that CD146bright defines the most undifferentiated HMSCs (20). The heterogeneity in level of commitment between the two subpopulations was therefore checked by reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis to quantify differences in the expression of differentiation markers. The analysis showed that the CD146dim cells expressed higher levels of osteogenic differentiation markers (i.e., RUNX-2) than the CD146bright cells (Fig. 3, F and G).

The level of RUNX-2 expression was also quantified at the protein level using immunocytochemistry and image analysis of the MBs on the microfluidic device by developing a layer-by-layer description of the MBs. This mapping was constructed by estimating the boundaries of each cell in the image from a Voronoi diagram, built around the positions of the cell nuclei stained with 4,6-diamidino-2-phenylindole (DAPI) (Fig. 4A) (22). These estimates were then used to associate the fluorescence signal from each cell with one of the concentric layers (Fig. 4B). Such a mapping provides better resolution for discriminating the spatial heterogeneity of protein expression than simply assigning a fluorescence signal to a defined radial coordinate (fig. S4). Moreover, the reliability of the measurements by quantitative image analysis was confirmed by performing several control experiments. In particular, we verified (i) the specificity of the fluorescence labeling, (ii) the absence of limitation for antibody diffusion, and (iii) the absence of the light path alteration in the 3D structure (fig. S5 and Materials and Methods). Consistent with the qPCR data, we found that HMSCs located at the boundaries of the MBs expressed higher levels of the protein RUNX-2 than the cells located in the core (see Fig. 4, C and D, and fig. S7 for individual experiments).

(A and B) The detection of nuclei within MBs enables the construction of a Voronoi diagram (A) that allows the identification of concentric cell layers (B) within the MBs. (C and D) Representative image (C) and quantitative analysis (D) (error bars represent the SD) of RUNX-2 staining within the cell layers of the MB (Nchips = 3 and nMBs = 458). N.S., nonsignificant. (E to H) Quantitative analysis (E) and representative images (F to H) of N-cadherin staining after methanol/acetone (F) (Nchips = 3 and nMBs = 405), after PFA/Triton X-100 fixation and permeabilization (G) (Nchips = 3 and nMBs = 649), and F-actin staining with phalloidin (H) (Nchips = 3 and nMBs = 421). Scale bars, 20 m. The images were acquired using a wide-field microscope. ***P < 0.001. (I) Schematized representation of the structural organization of MBs.

Thus, as CD146 defines the most undifferentiated and clonogenic cells as well as regulates the trilineage differentiation potential of HMSCs, the results indicate that HMSCs self-organize within MBs based on their initial commitment. The most undifferentiated and largest cells are found in the core (r/R < 0.8), while more differentiated cells positioned in the outer layers of the MBs (r/R > 0.8) (Fig. 4, C to E). In addition, these data reveal that HMSCs are conditioned a priori to occupy a specific location within the MBs.

The commitment of HMSCs is known to regulate their level of CD146 expression and the type of cell-cell adhesion molecules (23), which plays a fundamental role in the structural cohesion of the MBs (Fig. 2H). For this reason, we interrogated the organization of cell-cell junctions after the MB formation through measurements of the N-cadherin and F-actin fluorescence signal distribution. Two different protocols were used to discriminate several forms of N-cadherin interactions. First, paraformaldehyde (PFA) fixation and Triton X-100 permeabilization were used, because they were reported to retain in place only the detergent-insoluble forms of N-cadherin. Alternatively, ice-cold methanol/acetone fixation and permeabilization enabled the detection of all forms of N-cadherins (26). The results show a higher density of total N-cadherins in the core of the MBs (Fig. 4, E and F), while a higher density of F-actin was found in the cell layers located near the edge of the MBs (Fig. 4, E and H). The pattern of F-actin distribution was not related to the agarose gel surrounding the MBs (fig. S5B). These results are consistent with the theories of cell sorting in spheroids that postulate that more adhesive cells (i.e., expressing more N-cadherin or CD146) should be located in the core, while more contractile cells (i.e., containing denser F-actin) are located at the edge of the MBs (24). Moreover, our observations are in accordance with recent results demonstrating that HMSCs establishing higher N-cadherin interactions show reduced osteogenic commitment than HMSCs making fewer N-cadherin contacts, potentially through the modulation of Yap/Taz signaling and cell contractility (23).

In contrast, the most triton-insoluble forms of N-cadherins were located at the boundaries of the HMSC aggregates (Fig. 4, E and G), at the same position as the cells containing the denser F-actin. These results demonstrate that different types of cellular interactions were formed between the core and the edges of the MBs, which correlated with the degree of cell commitment that apparently stabilize the adherens junctions (Fig. 4I) (25).

We found above that the degree of commitment was linked with the pattern of HMSC self-organization in MBs (i.e., formation of adherens junctions), which may also regulate their paracrine functions (26). We therefore interrogated the functional consequences of the cellular organization in MBs by investigating the distribution of VEGF- and PGE2-producing cells.

The specific production of COX-2, VEGF, and two other molecules regulating bone homeostasis such as tumor necrosis factorinducible gene 6 (TSG-6) (27) and stanniocalcin 1 (STC-1) (28) was evaluated by RT-qPCR analysis. An increased transcription (20- to 60-fold) of these molecules was measured in 3D in comparison to the monolayer culture (Fig. 5, A and B). Consistent with this observation, while a very limited level of secreted PGE2 and VEGF was measured by enzyme-linked immunosorbent assay (ELISA) in 2D culture, they were significantly increased (by about 15-fold) upon the aggregation of HMSCs in 3D (Fig. 5C). In addition, to interrogate the specific role of COX-2 [the only inducible enzyme catalyzing the conversion of arachidonic acid into prostanoids; (29)] in PGE2 and VEGF production, indomethacin (a pan-COX inhibitor) was added to the culture medium. Indomethacin abrogated the production of PGE2, and it significantly decreased VEGF secretion (Fig. 5C), which suggests an intricate link between COX-2 expression and the secretion of these two molecules (30, 31).

(A and B) RT-qPCR analysis of the relative TSG-6, COX-2, STC-1, and VEGF expression to GADPH (Ct) (A) and relative RNA expression (B) in the 3D and 2D populations (n3D = 3 and n2D = 3). (C) Quantification by ELISA of the PGE-2 and VEGF secreted by hMSCs cultivated in 2D, as MBs or as MBs treated with indomethacin (nchips = 3 and n2D = 3). (D and E) Representative image (D) and quantitative analysis (E) of COX-2 (Nchips = 13 and nMBs = 2936) and (F) VEGF-A (Nchips = 3 and nMBs = 413) staining within the cell layers of the MBs (error bars represent the SD). Scale bars, 50 m. The images were acquired using a wide-field microscope *P < 0.05; ***P < 0.001; a and b: P < 0.05. (G) Schematized representation of the structural organization of MBs.

To further interrogate the link between the COX-2 and the VEGF-producing cells, their location was analyzed by quantitative image analysis at a layer-by-layer resolution. These measurements showed significantly higher levels of COX-2 in the first two layers, compared with the successive layers of the MBs (Fig. 5, D and E), with a continuous decrease of about 40% of the COX-2 signal between the edge and the core. This pattern of COX-2 distribution was not affected by the MB diameter (fig. S7B). Similar observations were made with VEGF (Fig. 5, D and F), demonstrating that cells at the boundaries of the MBs expressed both COX-2 and VEGF (Fig. 5G). Taken with the measurements of Fig. 5C, these results imply that COX-2 acts as an upstream regulator of PGE2 and VEGF secretion. Conversely, oxygen deprivation was unlikely to occur within the center of the MBs because no hypoxic area was detected through the whole MBs (fig. S5). Consequently, it is unlikely that hypoxia-inducible factor1 (HIF-1) signaling mediates the increase in VEGF expression at the boundaries of the MBs. Note that finding the link between these three molecules requires the 3D format, because the molecules are not detected in 2D. Here, the combination of population-scale measurements (Fig. 5C) and cell layer analysis (Fig. 5, E and F) provides strong evidence for this pathway.

Because variations of COX-2 and adherens junction distribution are colocalized within the MBs (Figs. 4, E to G, and 5, D and E), the results point to a link between the quality of cell-cell interactions and the spatial distribution of the COX-2high cells in 3D. The mechanisms leading to the spatial patterning of COX-2 expression in the MBs were therefore explored using inhibitors of the signaling pathways related to anti-inflammatory molecule production and of the molecular pathways regulating the structural organization (table S3): (i) 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) that inhibits NF-B, a critical transcription factor regulating the level of COX-2 expression (32); (ii) N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) that inhibits the canonical Notch pathway, modulating cell-cell interactions and several differentiation pathways; (iii) Y-27632 (Y27) that inhibits ROCK involved in the bundling of F-actin (i.e., formation of stress fibers) to assess the role of actomyosin organization; and (iv) cytochalasin D (CytoD) that inhibits the polymerization of actin monomers.

While the addition of DAPT had virtually no effect on the ability of the cells to form MBs, Y27 led to MBs with more rounded cells, and both QNZ and CytoD strongly interfered with the MB formation process (Fig. 6, A to C). The results indicate that NF-B activation and the promotion of actin polymerization are critical signaling steps initiating the process of MB formation by HMSCs.

(A) Representative images of MBs formed 1 day after the droplet loading. Scale bar, 100 m. Inhibitors are added to the culture medium before the MB formation. (B and C) Quantitative analysis of the aggregates projected area (B) and shape index (C) in the presence of the different inhibitors. Red lines represent the mean value for each condition. (D and E) Representative images (D) (contrast is adjusted individually for a better visualization of the pattern; scale bar, 100 m; the images were acquired using a wide-field microscope) and quantitative analysis (E) of the COX-2 fluorescence signal intensity normalized by the control value with the different inhibitors. For these longer culturing times, QNZ and CytoD are only added during the phase change to allow the MB formation. Small dots represent one MB. Large dots represent the average normalized COX-2 fluorescence signal per chip. Each color corresponds to a specific chip. *P < 0.05. (F) Estimation of inhibitor effect in the cell layers with the COX-2 signal normalized by the control value. Control: Nchips = 11 and nMBs = 2,204; QNZ: Nchips = 6 and nMBs = 1215; DAPT: Nchips = 3 and nMBs = 658; Y27: Nchips = 4 and nMBs = 709; CytoD: Nchips = 3 and nMBs = 459. *P < 0.05; **P < 0.01; ***P < 0.001. (G) Proposed mechanisms regulating the MB formation and the patterning of their biological functions. (i) Regulation of the formation of MBs. (ii and iii) Spatial patterning of hMSC biological properties within MBs.

To assess the role of NF-B and actin polymerization in the pattern and the level of COX-2 expression in the MBs, QNZ and CytoD were added 1 day after the cell seeding, once the MBs were completely formed. In contrast, Y27 and DAPT were included in the initial droplets and maintained in the culture medium for the whole culture period. Typical images showing the COX-2 signal in these different conditions are shown in Fig. 6D (see also fig. S7 for quantification of the individual experiments). Of note, none of the inhibitors had an effect on Casp3 activation, indicating that they do not induce apoptosis at the concentration used in this study (fig. S8). The levels of COX-2 expression in MBs, after 3 days in culture, were significantly reduced with QNZ, also decreasing after the addition of CytoD (Fig. 6E). By contrast, Y27 and DAPT had no effect on the levels of COX-2 expression. As a consequence, the results demonstrate that a sustained NF-B activity after the MB formation is required to promote COX-2 expression. Moreover, the induction of actin polymerization in MBs constitutes a mandatory step to initiate COX-2 production.

To get a deeper understanding on the local regulation of these signaling pathways, we analyzed at the single-cell resolution the distribution of COX-2 within the MBs. The spatial mapping revealed that the COX-2 fluorescence intensity was mostly attenuated at the edge of the MBs treated with CytoD and QNZ, while more limited change in the pattern of its expression was observed in the presence of Y27 and even less so with DAPT (Fig. 6F). Consequently, the results revealed a strong link between cell phenotype, the capability to form functional adherens junctions, and the local regulation of NF-B and actin polymerization leading to the increased expression of PGE2 and VEGF that are mediated by COX-2 in 3D (Fig. 6G). Together, the results indicate that in 3D cell aggregates, the spatial organization has some implications on the specific activation of signaling pathways, resulting in local functional heterogeneity.

Understanding the mechanisms of the formation and the spatial tissue patterning within organoids requires a characterization at single-cell level in 3D. In this study, we used a novel microfluidic and epifluorescence imaging technology to obtain a precise quantitative mapping of the structure, the position, and the link with individual cell functions within MBs. The image analysis provided quantitative data that were resolved on the scale of the individual cells, yielding measurements on 700,000 cells in situ within over 10,000 MBs.

While the microfluidic technology developed here is very efficient for high-density size-controlled MB formation, the method is prone to some limitations. Chief among them, the cultivation in nanoliter-scale drops may subject the cells to nutrient deprivation and by-product accumulation under static culture conditions. This limits the duration of the culture to a few days, depending on the cell type and droplet size. To overcome this limitation, it is possible to continuously perfuse the chip with fresh culture medium after performing the oil-aqueous phase exchange, as we demonstrated previously (16). Alternatively, it is also possible to maintain the cells in liquid droplets (without using a hydrogel) by resupplying culture medium through the fusion of additional drops at later times. This operation requires, however, a new design of the anchors and additional microfluidic steps (21).

The second major drawback of the method emerges from the large distance between the MBs and the microscope objective, which requires the use of very large working distance objectives. This compounds the difficulty of applying different confocal techniques by limiting the fluorescence intensity of the images, which, in turn, reduces the throughput when 3D image stacks are required. Although we have shown above that wide-field imaging can be used to obtain spatial mappings of spheroid structure and cell functions, true single-cell measurements will need to overcome the limitations on imaging in the future.

A Voronoi segmentation was used to categorize the cells into concentric layers, starting from the edge of the MBs and ending with the cells in the central region (22), which allowed us to measure variations in the structural organization and in the protein expressions on a layer-by-layer basis within the 3D cultures. The MBs were found to organize into a core region of undifferentiated cells, surrounded by a shell of committed cells. This hierarchical organization results from the spatial segregation of an initially heterogeneous population, as is generally the case for populations of pluripotent and somatic stem cells (2, 3, 33). The process of aggregation of HMSCs obtained within a few hours takes place through different stages (Fig. 6G): The first steps of the aggregation of MBs are mediated by N-cadherin interactions. In parallel, NF-B signaling is activated, promoting cell survival by preventing anoikis of suspended cells (34, 35). At later stages, the formation of polymerized F-actin and, to a lesser extent, stress fibers mediates the MB compaction, mainly at the edge of the MBs where the cellular commitment helps the stabilization of adherens junctions. The formation of adherens junctions facilitates the cohesion of the 3D structure, probably through the enhanced - and -catenin availability in the CD146dim/RUNX-2+ cells (36, 37, 38), which are recruited in the CCC complexes of the adherens junctions to promote the stable coupling of the F-actin to the N-cadherin (39), which become more insoluble to Triton X-100 than unbounded N-cadherins.

A functional phenotype that correlates with this hierarchical segregation is an increase in endocrine activity of the cells located at the boundaries of the MBs. COX-2 expression is increased in the outer layers of the MBs, which also contain more functional adherens junctions as well as a sustained NF-B activity in this region. The promoter of COX-2 contains RUNX-2 and NF-B cis-acting elements (40). While RUNX-2 is required for COX-2 expression in mesenchymal cells, its level of expression does not regulate the levels of COX-2 (40). The increased COX-2 expression is, in turn, due to the unbundled form of F-actin (i.e., a more relaxed form of actin, in comparison to the dense stress fibers observed in 2D) near the edge of the MBs, which was reported to sustain NF-B activity (41) and to down-regulate COX-2 transcriptional repressors (42). Therefore, NF-B has a high activity in the outer layers of the MB, where it locally promotes COX-2 expression.

These results show that the 3D culture format may provide some insights to understand the mesenchymal cell behavior in vivo, because we found that the expression of key bone regulatory molecules is spatially regulated as a function of the structural organization of the MBs. The 3D structure obtained here recalls some of the conditions found at the initial steps of intramembranous ossification that occurs after mesenchymal condensation (i.e., no chondrogenic intermediate was found in the MBs). In the developing calvaria, the most undifferentiated mesenchymal cells (e.g., Sca-1+/RUNX-2 cells) are located in the intrasutural mesenchyme, which is surrounded by an osteogenic front containing more committed cells (e.g., Sca-1/RUNX-2+ cells) (43, 44). Similarly, we observed that undifferentiated HMSCs (i.e., CD146bright/RUNX-2 HMSCs) were surrounded by osteogenically committed cells (i.e., CD146dim/RUNX-2+ HMSCs), which also coexpressed pro-osteogenic molecules, namely, COX-2 and its downstream targets, PGE2 and VEGF. While the link between COX-2 and PGE2 is well established, there is also evidence that COX-2 can induce the production of VEGF in different cell types, e.g., colon cancer cells (45), prostate cancer cells (46), sarcoma (47), pancreatic cancer cells (48), retinal Mller cells (49), gastric fibroblasts (50), skin or lung fibroblasts (51). In these cases, the mechanism for VEGF production through COX-2 induction is thought to be linked to PGE-2, either in an autocrine/paracrine manner (52) or in an intracrine manner (53).

Beyond HMSCs, spatial organization related to the level of differentiation and cell size has been documented in growing embryoids and organoids, with more committed cells being positioned in the outer layers (54, 55, 56). Our results show that a similar hierarchical structure can also be obtained through the aggregation of a mixed population of adult progenitors. This suggests that cell sorting, based on the size and commitment, plays a dominant role in organizing stem cell aggregates. This data-driven approach of combining high-throughput 3D culture and multiscale cytometry (16) on complex biological models can be applied further for getting a better understanding of the equilibria that determine the structure and the function of cells within multicellular tumor spheroids, embryoid bodies, or organoids.

HMSCs derived from the Whartons jelly of the UC (HMSCs) [American Type Culture Collection (ATCC) PCS-500-010, LGC, Molsheim, France] were obtained at passage 2. Four different lots of HMSCs were used in this study (lot nos. 60971574, 63739206, 63516504, and 63739206). While the lots were not selected a priori, we found consistent results for COX-2 and CD146 distribution within MBs. HMSCs from the different lots were certified for being CD29, CD44, CD73, CD90, CD105, and CD166 positive (more than 98% of the population is positive for these markers) and CD14, CD31, CD34, and CD45 negative (less than 0.6% of the population is positive for these markers) and to differentiate into adipocytes, chondrocytes, and osteocytes (ATCC, certificates of analysis). HMSCs were maintained in T175 cm2 flasks (Corning, France) and cultivated in a standard CO2 incubator (Binder, Tuttlingen, Germany). The culture medium was composed of modified Eagles medium (-MEM) (Gibco, Life Technologies, Saint Aubin, France) supplemented with 10% (v/v) fetal bovine serum (FBS) (Gibco) and 1% (v/v) penicilin-streptomycin (Gibco). The cells were seeded at 5 103 cells/cm2, subcultivated every week, and the medium was refreshed every 2 days. HMSCs at passage 2 were first expanded until passage 4 [for about five to six population doublings (PDs)], then cryopreserved in 90% (v/v) FBS/10% (v/v) dimethyl sulfoxide (DMSO), and stored in a liquid nitrogen tank. The experiments were carried out with HMSCs at passages 4 to 11 (about 24 to 35 PDs, after passage 2).

HMSCs were harvested by scrapping or trypsinization from T175 cm2 flasks. Then, the cells were incubated in staining buffer [2% FBS in phosphate-buffered saline (PBS)], stained with a mouse anti-human CD146Alexa Fluor 647 (clone P1-H12, BD Biosciences), a mouse anti-human CD31Alexa Fluor 488 (BD Biosciences, San Jose, CA) antibody, a mouse anti-human CD105Alexa Fluor 647 (BD Biosciences, San Jose, CA), a mouse anti-human CD90fluorescein isothiocyanate (FITC) and a mouse anti-human CD73allophycocyanin (APC) (Miltenyi Biotec, Germany), a CD14-APC (Miltenyi Biotec), a CD34-FITC (BioLegend), and an HLA-DRAPC (BD Biosciences).

The percentages of CD73-, CD90-, CD105-, CD146-, CD31-, CD34-, and HLA-DRpositive cells were analyzed using a FACS LSRFortessa (BD Biosciences, San Jose, CA) or an ImageStream (Amnis) flow cytometer. To validate the specificity of the antibody staining, the distributions of fluorescently labeled cells were compared to cells stained with isotype controls: mouse immunoglobulin G1 (IgG1), k-PE-Cy5 (clone MOPC-21, BD Biosciences), and mouse IgG2a K isotype control FITC (BD Biosciences, San Jose, CA). Alternatively, HMSCs were sorted on the basis of their level of expression of CD146 or their size [forward scatter (FSC) and side scatter (SSC)] using a FACSAria III (BD Biosciences, San Jose, CA).

To induce adipogenic differentiation, UC-HMSCs were seeded at 1 104 cells/cm2 in culture medium. The day after, the culture medium was switched to StemPro Adipogenesis Differentiation medium (Life Technologies) supplemented with 10 M rosiglitazone (Sigma-Aldrich) for 2 weeks. To visualize the differentiated adipocytes, the cells were stained with Oil Red O (Sigma-Aldrich). As a control, UC-HMSCs were maintained in culture medium for 2 weeks and stained with Oil Red O, as above.

To induce osteogenic differentiation, UC-HMSCs were seeded at 5 103 cells/cm2 in culture medium. The day after, the culture medium was switched to StemPro Osteogenesis Differentiation medium (Life Technologies) supplemented with 2-nm bone morphogenetic protein 2 (BMP-2) (Sigma-Aldrich) for 2 weeks. To visualize the differentiated osteoblasts, the cells were stained with Alizarin Red S (Sigma-Aldrich). As a control, UC-HMSCs were maintained in culture medium for 2 weeks and stained with Alizarin Red S, as above.

To induce chondrogenic differentiation, UC-HMSCs were seeded at 1 106 cells/ml in a 15-ml conical tube to promote micromass culture. The medium consisted of StemPro Chondrogenic Differentiation medium (Life Technologies). After 3 weeks in culture, the pellets were fixed and cryosectioned and then stained for Alcian Blue 8GX (Sigma-Aldrich). As a control, UC-HMSCs were maintained in 2D using culture medium for 3 weeks and stained with Alcian Blue, as above.

The color images were acquired using a binocular (SMZ18, Nikon) equipped with a camera (D7500, Nikon).

Standard dry-film soft lithography was used for the flow-focusing device (top of the chip) fabrication, while a specific method for the fabrication of the anchors (bottom of the chip) was developed. For the first part, up to five layers of dry-film photoresist consisting of 50-m Eternal Laminar E8020, 33-m Eternal Laminar E8013 (Eternal Materials, Taiwan), and 15-m Alpho NIT215 (Nichigo-Morton, Japan) negative films were successively laminated using an office laminator (PEAK pro PS320) at a temperature of 100C until the desired channel height, either 135, 150, 165, or 200 m, was reached. The photoresist film was then exposed to ultraviolet (Lightningcure, Hamamatsu, Japan) through a photomask of the junction, the channels, and the culture chamber boundaries. The masters were revealed after washing in a 1% (w/w) K2CO3 solution (Sigma-Aldrich). For the anchor fabrication, the molds were designed with RhinoCAM software (MecSoft Corporation, LA) and were fabricated by micromilling a brass plate (CNCMini-Mill/GX, Minitech Machinery, Norcross). The topography of the molds and masters was measured using an optical profilometer (Veeco Wyco NT1100, Veeco, Mannheim, Germany).

For the fabrication of the top of the chip, poly(dimethylsiloxane) [PDMS; SYLGARD 184, Dow Corning, 1:10 (w/w) ratio of curing agent to bulk material] was poured over the master and cured for 2 hours at 70C. For the fabrication of the bottom of the chip, the molds for the anchors were covered with PDMS. Then, a glass slide was immersed into uncured PDMS, above the anchors. The mold was lastly heated on a hot plate at 180C for 15 min. The top and the bottom of the chip were sealed after plasma treatment (Harrick, Ithaca). The chips were filled three times with Novec Surface Modifier (3M, Paris, France), a fluoropolymer coating agent, for 30 min at 110C on a hot plate.

HMSCs were harvested with TrypLE at 60 to 70% confluence, and a solution containing 6 105 cells in 70 l of medium was mixed with 30 l of a 3% (w/v) liquid low-melting agarose solution (i.e., stored at 37C) (Sigma-Aldrich, Saint Quentin Fallavier, France) diluted in culture medium containing gentamicin (50 g/ml; Sigma-Aldrich) (1:3, v/v), resulting in a 100-l solution of 6 106 cells/ml in 0.9% (w/v) agarose.

HMSCs and agarose were loaded into a 100-l glass syringe (SGE, Analytical Science, France), while Fluorinert FC-40 oil (3M, Paris, France) containing 1% (w/w) PEG-di-Krytox surfactant (RAN Biotechnologies, Beverly, USA) was loaded into a 1- and 2.5-ml glass syringes (SGE, Analytical Science). Droplets of cell-liquid agarose were generated in the FC-40 containing PEG-di-Krytox, at the flow-focusing junction, by controlling the flow rates using syringe pumps (neMESYS Low-Pressure Syringe Pump, Cetoni GmbH, Korbussen, Germany) (table S1). After complete loading, the chips were immersed in PBS, and the cells were allowed to settle down and to organize as MBs overnight in the CO2 incubator. Then, the agarose was gelled at 4C for 30 min, after which the PEG-di-Krytox was extensively washed in flushing pure FC-40 in the culture chamber. After washing, cell culture medium was injected to replace the FC-40. All flow rates are indicated in table S1. Further operations were allowed by gelling the agarose in the droplets, such that the resulting beads were retained mechanically in the traps rather than by capillary forces (Fig. 2G). This step allowed the exchange of the oil surrounding the droplets by an aqueous solution, for example, to bring fresh medium for long-term culture, chemical stimuli, or the different solutions required for cell staining.

For the live imaging of the MB formation, the chips were immersed in PBS and then were incubated for 24 hours in a microscope incubator equipped with temperature, CO2, and hygrometry controllers (Okolab, Pozzuoli, Italy). The cells were imaged every 20 min.

2D cultures or MBs were washed in PBS and incubated with a 5 M NucView 488 caspase-3 substrate (Interchim, Montluon, France) diluted in PBS. After washing with PBS, HMSCs were fixed with a 4% (w/v) PFA (Alpha Aesar, Heysham, UK) for 30 min and permeabilized with 0.2 to 0.5% (v/v) Triton X-100 (Sigma-Aldrich) for 5 min. The samples were blocked with 5% (v/v) FBS in PBS for 30 min and incubated with a rabbit polyclonal antiCOX-2 primary antibody (ab15191, Abcam, Cambridge, UK) diluted at 1:100 in 1% (v/v) FBS for 4 hours. After washing with PBS, the samples were incubated with an Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG secondary antibody (A-11012, Life Technologies, Saint Aubin, France) diluted at 1:100 in 1% (v/v) FBS for 90 min. Last, the cells were counterstained with 0.2 M DAPI for 5 min (Sigma-Aldrich) and then washed with PBS.

The same protocol was used for the staining of VEGF-Aexpressing cells using a rabbit anti-human VEGF-A monoclonal antibody (ab52917, Abcam, Cambridge, UK), which was revealed using the same secondary antibody as above. RUNX-2positive cells were similarly stained using a mouse anti-human RUNX-2 monoclonal antibody (ab76956, Abcam, Cambridge, UK), which was revealed using an Alexa Fluor 488 goat anti-mouse IgG2a secondary antibody (A-21131, Life Technologies, Saint Aubin, France), both diluted at 1:100 in 1% (v/v) FBS.

To measure potential induction of hypoxia within the core of the MBs, the cells were stained with Image-iT Red Hypoxia Reagent (Invitrogen) for 3 hours and then imaged using a fluorescence microscope. As a positive control, the chips containing the MBs were immersed into PBS, incubated overnight in an incubator set at 37C under 3% O2/5% CO2, and lastly imaged as above.

To interrogate the contribution of signaling related to anti-inflammatory molecule production (COX-2 and NF-B) or molecular pathways regulated by the cell structural organization (Notch, ROCK, and F-actin), several small molecules inducing their inhibition were added to the culture medium (table S1). For all the conditions, the final concentration of DMSO was below 0.1% (v/v) in the culture medium.

The cell viability was assessed using LIVE/DEAD staining kit (Molecular Probes, Life Technologies). The MBs were incubated for 30 min in PBS containing 1 M calcein AM and 2 M ethidium homodimer-1, in flushing 100 l of the solution. The samples were then washed with PBS and imaged under a motorized fluorescence microscope (Nikon, France).

For the detection of the functional forms of N-cadherins (i.e., the N-cadherins closely linked to the actin network, which are PFA insoluble), the MBs were fixed with a 4% (w/v) PFA (Alpha Aesar, Heysham, UK) for 30 min and permeabilized with 0.2 to 0.5% (v/v) Triton X-100 (Sigma-Aldrich) for 5 min. Alternatively, the aggregates were incubated for 5 min with 100% cold methanol followed by 1 min with cold acetone, for the detection of total N-cadherins (i.e., the PFA-soluble and PFA-insoluble forms).

Then, the samples were blocked with 5% (v/v) FBS in PBS for 30 min and incubated with a rabbit polyclonal antiN-cadherin primary antibody (ab18203, Abcam, Cambridge, UK) diluted at 1:100 in 1% (v/v) FBS for 4 hours. After washing with PBS, the samples were incubated with an Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG secondary antibody (A-11012, Life Technologies, Saint Aubin, France) diluted at 1:100 in 1% (v/v) FBS for 90 min. Last, the cells were counterstained with 0.2 M DAPI for 5 min (Sigma-Aldrich) and then washed with PBS.

For the quantification of the polymerized form of actin (F-actin), the MBs were first fixed with a 4% (w/v) PFA (Alpha Aesar, Heysham, UK) for 30 min and permeabilized with 0.2 to 0.5% (v/v) Triton X-100 (Sigma-Aldrich) for 5 min. The samples were then blocked with a 5% (v/v) FBS solution and incubated for 90 min in a 1:100 phalloidinAlexa Fluor 594 (Life Technologies) diluted in a 1% (v/v) FBS solution. The cells were then counterstained with 0.2 M DAPI for 5 min (Sigma-Aldrich) and then washed with PBS.

To ensure the specificity of the antibody to COX-2 and N-cadherin, control UC-HMSCs were permeabilized, fixed, and incubated only with the secondary antibody (Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG), as above. The absence of fluorescence signal indicated the specific staining for intracellular COX-2 and N-cadherin.

Next, to validate that the distribution of the fluorescence intensity was not related to any antibody diffusion limitation, the MBs were fixed and permeabilized, as above. For this assay, the MBs were not subjected to any blocking buffer. The cells were incubated for 90 min with the Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG secondary antibody (A-11012, Life Technologies, Saint Aubin, France) diluted at 1:100 in 1% (v/v) FBS. Then, the cells were counterstained for DAPI, as above. Last, the MBs were collected from the chip, deposed on a glass slide, and imaged.

For the analysis of COX-2 expression by flow cytometry, the total MBs were recovered from the chip. The MBs were then trypsinized and triturated to obtain single-cell suspension. UC-HMSCs were stained for COX-2, as above. The percentage of COX-2positive cells was quantified on 5 103 dissociated UC-HMSCs using a Guava easyCyte Flow Cytometer (Merck Millipore, Guyancourt, France). The results were compared to the fluorescence intensity distribution obtained by image analysis.

To interrogate the influence of the MB opacity in the COX-2 and N-cadherin fluorescence signals, the samples were treated by the Clear(T2) method after immunostaining (57). Briefly, the MBs were incubated for 10 min in 25% (v/v) formamide/10% (w/v) polyethylene glycol (PEG) (Sigma-Aldrich), then for 5 min in 50% (v/v) formamide/20% (w/v) PEG, and lastly for 60 min in 50% (v/v) formamide/20% (w/v) PEG, before their imaging. The fluorescence signal distribution was compared with the noncleared samples.

The MBs were collected from the chip and then fixed using PFA, as above. The MBs were incubated overnight in a 30% sucrose solution at 4C. Then, the sucrose solution was exchanged to O.C.T. medium (optimal cutting temperature; Tissue-Tek) in inclusion molds, which were slowly cooled down using dry ice in ethanol. The molds were then placed at 80C. On the day of the experiments, the O.C.T. blocks were cut at 7 m using a cryostat (CM3050 S, Leica). The cryosections were placed on glass slides (SuperFrost Plus Adhesion, Thermo Fisher Scientific), dried at 37C, and rehydrated using PBS. The cryosections were permeabilized and stained for COX-2, as above. The slides were lastly mounted in mounting medium containing DAPI (Fluoromount-G, Invitrogen).

All the images used for the quantitative analysis were taken using a motorized wide-field microscope (Ti, Eclipse, Nikon), equipped with a CMOS (complementary metal-oxide semiconductor) camera (ORCA-Flash4.0, Hamamatsu) and a fluorescence light-emitting diode source (Spectra X, Lumencor). The images were taken with a 10 objective with a 4-mm working distance (extra-long working distance) and a 0.45 numerical aperture (NA) (Plan Apo , Nikon).

For control experiments, images were taken using a motorized (Ti2, Nikon) confocal spinning disc microscope equipped with lasers (W1, Yokogawa) and the same camera and objective as above. Alternatively, the samples were imaged with a multiphoton microscope (TCS SP8 NLO, MP, Leica). The objective was an HCX PL APO CS 10, 0.40 NA, working distance of 2.2 mm (Leica).

All immunostained samples were counterstained with DAPI, and most of the images (i.e., for N-cadherin, COX-2, VEGF-A, and F-actin) were taken using red light excitation that is known to penetrate deeper into the 3D objects than dyes emitting at lower weight length (e.g., DAPI, FITC). For wide-field microscopy, the focal plane was defined as the area containing the maximal number of DAPI-stained nuclei covering the focal area, while z stacks were taken for the whole in-focus planes containing DAPI-stained nuclei using spinning discs and two-photon confocal microscopy.

Wide-field imaging is sensitive for the emission of fluorescence from inside and outside the focal plane (i.e., from the out-of-focus upper and bottom planes of the spheroids) (58). Consistently, more DAPI signal from nuclei is emitted from the core than in the edges of MBs using epifluorescence microscopy (fig. S5I). We confirmed that our interpretation of the signal distribution from epifluorescence images was consistent with confocal and two-photon microscopy by comparing with images taken from the median z plane and the maximal z projection (fig. S5, N to P).

Consequently, the results unambiguously demonstrate that even if there are more cells in the z plane of the middle area of the MBs, the contribution of the out-of-focus signal from N-cadherin, COX-2, VEGF-A, and F-actin staining in this area of the MBs is minimal using wide-field imaging. Because of the higher throughput of wide-field microscopy, this method was chosen to quantitatively analyze the distribution of these immunolabeled proteins within MBs.

The culture supernatants of six-well plates were collected, while the total medium content of the chip was recovered by flushing the culture chamber with pure oil. A PGE2 human ELISA kit (ab133055, Abcam, Cambridge, UK) was used for the quantification of PGE2 concentration in the culture supernatant, following the manufacturers instructions. Briefly, a polynomial standard curve of PGE2 concentration derived from the serial dilution of a PGE2 standard solution was generated (r2 > 0.9). The absorbance was measured using a plate reader (Chameleon, Hidex, Finland).

A VEGF-A human ELISA kit (Ab119566, Abcam, Cambridge, UK) was used for the quantification of VEGF-A concentration in the culture supernatant of 2D cultures or from the chips. A linear standard curve of VEGF-A concentration derived from the serial dilution of a VEGF-A standard solution was generated (r2 > 0.9). The absorbance was measured using a plate reader (Chameleon, Hidex, Finland).

The total MBs of a 3-day culture period were harvested from the chips, as described above. Alternatively, cells cultured on regular six-well plates were recovered using trypsin after the same cultivation time; CD146dim and CD146bright isolated cells were immediately treated for RNA extraction after sorting. The total RNA of 1 104 cells were extracted and converted to complementary DNA (cDNA) using SuperScript III CellsDirect cDNA Synthesis System (18080200, Invitrogen, Life Technologies), following the manufacturers instructions. After cell lysis, a comparable quality of the extracted RNA was observed using a bleach agarose gel, and similar RNA purity was obtained by measurement of the optical density at 260 and 280 nm using a NanoDrop spectrophotometer (Thermo Fisher Scientific, Wilmington, DE) between total RNA preparations from 2D and on-chip cultures.

The cDNA was amplified using a GoTaq qPCR Master Mix (Promega, Charbonnieres, France) or a FastStart Universal SYBR Green Master Mix (containing Rox) (Roche) and primers (Life Technologies, Saint Aubin, France or Eurofins Scientific, France) at the specified melting temperature (Tm) (table S2) using a MiniOpticon (Bio-Rad) or a QuantStudio 3 (Thermo Fisher Scientific) thermocycler. As a negative control, water and total RNA served as template for PCR. To validate the specificity of the PCR, the amplicons were analyzed by dissociation curve and subsequent loading on a 2.5% (w/v) agarose gel and migration at 100 V for 40 min. The PCR products were revealed by ethidium bromide (Sigma-Aldrich) staining, and the gels were imaged using a transilluminator. The analysis of the samples not subjected to reverse transcription (RT) indicated negligible genomic DNA contamination (i.e., <0.1%), while no amplification signal was observed for the water template (no template control). The amount of TSG-6, COX-2, STC-1, VEGF-A, RUNX-2, CEBP-, and SOX-9 transcripts was normalized to the endogenous reference [glyceraldehyde-3-phosphate dehydrogenase (GADPH)], and the relative expression to a calibrator (2D cultures) was given by 2Ct calculation. At least five biological replicates of 2D and on-chip cultures were analyzed by at least duplicate measurements. The standard curves for GADPH, TSG-6, COX-2, and STC-1 were performed using a five serial dilution of the cDNA templates and indicated almost 100% PCR efficiency.

The image analysis allowed us to perform a multiscale analysis (16) of the MBs. For each chip, single images of the anchors were acquired automatically with the motorized stage of the microscope. The analysis was conducted on a montage of the detected anchors using a custom MATLAB code (r2016a, MathWorks, Natick, MA). Two distinct routines were used: one with bright-field detection and one for the fluorescence experiments.

For the bright field-detection described previously (16), the cells were detected in each anchor as pixels with high values of the intensity gradient. This allowed for each cell aggregate to compute morphological parameters such as the projected area A and the shape index SI that quantifies the circularity of an objectSI=4APwhere P is the perimeter. Shape index values range from 0 to 1, with 1 being assigned for perfect disk.

The MB detection with fluorescence staining (DAPI/Casp3/COX-2, DAPI/phalloidin, DAPI/N-cadherin, or LIVE/DEAD) was performed as described previously (16). First, morphological data were extracted at the MB level, such as the equivalent diameter of the MBs or the shape index. Also, the mean fluorescence signal of each MB was defined as the subtraction of the local background from the mean raw intensity.

At the cellular level, two different methods were used, both relying on the detection of the nuclei centers with the DAPI fluorescence signal. On the one hand, each cell location could be assigned to a normalized distance from the MB center (r/R) to correlate a nuclear fluorescence signal with a position in the MB, as previously described (16). On the other hand, the cell shapes inside the MBs were approximated by constructing Voronoi diagrams on the detected nuclei centers. Basically, the edges of the Voronoi cells are formed by the perpendicular bisectors of the segments between the neighboring cell centers. These Voronoi cells were used to quantify the cellular cytoplasmic signal (COX-2, F-actin and N-cadherin, VEGF and RUNX-2). In detail, to account for the variability of the cytoplasmic signal across the entire cell (nucleus included), the fluorescence signal of a single cell was defined as the mean signal of the 10% highest pixels of the corresponding Voronoi cell.

Image processing was also used to get quantitative data on 2D cultures, as previously described (16). Last, different normalization procedures were chosen in this paper. When an effect was quantified compared with a control condition, the test values were divided by the mean control value, and the significance was tested against 1. For some other data, the values were simply normalized by the corresponding mean at the chip level to discard the interchip variation from the analysis.

*P < 0.05; **P < 0.01; ***P < 0.001; NS, nonsignificant. Details of each statistical test and P values can be found in table S4.

Acknowledgments: C. Frot is gratefully acknowledged for the help with the microfabrication, and F. Soares da Silva is gratefully acknowledged for the help in flow cytometry. The group of Biomaterials and Microfluidics (BMCF) of the Center for Innovation and Technological Research as well as the Center for Translational Science (CRT)Cytometry and Biomarkers Unit of Technology and Service (CB UTechS is also acknowledged for the access to the microfabrication and flow cytometry platform at the Institut Pasteur). Funding: The research leading to these results received funding from the European Research Council (ERC) grant agreement 278248 Multicell. Author contributions: S.S., C.N.B., and A.C. conceived the experiments. S.S. performed the experiments. R.F.-X.T. wrote the image processing code and performed the image analysis. R.F.-X.T., S.S., G.A., and A.B. performed the image and data analyses. S.S., C.N.B., and A.C. discussed the results and wrote the manuscript. All authors discussed the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Mapping the structure and biological functions within mesenchymal bodies using microfluidics - Science Advances

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Most of you reading this would have probably never heard of such a disease. My hope is, after taking time to read this, that you will know what myeloma is and have a better understanding of bone marrow cancer in general.

So, lets get started!

Your bone marrow is the factory where all your blood cells are made. This includes red blood cells (they carry the oxygen in your blood), white blood cells (your bodys defence against infections) and platelets (small fragments that prevent and stop bleeding).

The production of these cells by the bone marrow is very well controlled by your body, both in terms of the amount and the type of cells produced. If you have an infection, for instance, your body tells the stem cells in your bone marrow to make more white blood cells to help fight the infection. In such instances, an immature, baby cell gets produced in your bone marrow which then needs to go through various stages of growth and development to become a mature white blood cell. It is then released from the bone marrow into your bloodstream to go and do the job it was destined for, to fight the infection.

This process usually runs quite smoothly, but things can, unfortunately go horribly wrong. Sometimes your body makes a mistake in the production of a white blood cell, almost like a programming error which occurs in the DNA (blueprint) of the cell. It often recognizes its mistake and corrects it, but occasionally this abnormal cell has the ability to hide from your bodys defences, doesnt listen to your bodys commands anymore and can start to increase in number without anything controlling it. This causes a variety of problems and is then called cancer.

Depending on the type of white blood cell and where in its development the programming error occurs, a person can either develop a type of bone marrow cancer (usually leukaemia or myeloma) or lymphoma (glandular cancer), which is also a type of cancer that develops from an abnormal white blood cell.

That brings us to myeloma (also called multiple myeloma or plasma cell myeloma). Myeloma is a type of bone marrow cancer that develops when a programming error occurs in the development of a specific type of white blood cell, called a plasma cell. To understand myeloma better, it is important to understand what role a plasma cell plays under normal circumstances.

They are indeed an integral part of your bodys immune system. Any infection that you may develop gets recognized by your plasma cells. They respond by rapidly producing small proteins called antibodies, which are almost like homing missiles, programmed to go and destroy only that specific virus or bacteria that is making you ill.

After an infection, some of the antibodies remain in your bloodstream and if you are exposed to that exact virus or bacteria again, they are ready to attack immediately, thereby limiting the infection. This is the rationale behind childhood vaccination; to stimulate the production of antibodies which patrol your bloodstream and protect you when you get exposed to infections like measles, polio and many others.

If these plasma cells become cancerous however, they rapidly increase in number, taking over the bone marrow and producing a massive amount of an abnormal antibody which can cause a whole array of problems. This increase in antibody levels in the bloodstream can be measured with a blood test and is also used to monitor the response to treatment.. What are thesymptoms of myeloma?

The abnormal plasma cells in the bone marrow overwhelms the normal bone marrow which most commonly leads to an inability to produce enough red blood cells. This is called anaemia. Symptoms of anaemia are related to the bodys inability to carry sufficient oxygen to your organs and include worsening fatigue, shortness of breath and dizziness.

The abnormal plasma cells also have the ability to weaken your bones. This can either be a generalized loss of bone strength (called osteoporosis), or it can lead to numerous holes being eaten in your bones. This can be seen on an X-Ray or other types of scans. It often results in significant bone pain or even worse, severe fractures with minimal- or even no trauma at all.

Bones are rich in calcium, and if they are being eaten away, their calcium content is released into the bloodstream causing an elevated blood calcium level. This can lead to dehydration, kidney failure and numerous other symptoms.

As mentioned before, the plasma cells in the bone marrow releases a massive amount of abnormal antibodies into the bloodstream. They can clog up your kidneys and cause significant- and often irreversible kidney failure. This can seriously complicate the management of the disease.

These are by far the most common features of myeloma:

Anaemia, bone lesions or fractures, hypercalcaemia and kidney failure.There are numerous other symptoms which can occur, albeit less common.

Is myeloma treatable?

Myeloma is indeed a treatable condition, but there are a couple of important treatment principles to understand.

For most people, myeloma is not a curable disease. It can, however, be carefully managed and the aim of treatment is to provide a good quality of life for as many years as possible. No patients disease is the same and where we sometimes have patients with myeloma living in excess of ten years after being diagnosed, other patients are unfortunately less fortunate and have a form of the disease that is resistant to treatment which can take its toll after only a couple of months.

We perform DNA-tests on the cancer cells and look at various other blood results in an attempt to identify those patients with high-risk disease, who potentially need more intense treatment than others.

The goal of treatment is to destroy as many abnormal plasma cells in the bone marrow as possible. This leads to recovery of the normal bone marrow and minimises the risk of any further complications, giving the body a chance to recover from any complications caused prior to treatment.

For many decades, the backbone of the treatment for myeloma was a combination of two different type of drugs: Chemotherapy and high dosages of cortisone. This is usually quite well tolerated.

The last couple of years, however, have seen an explosion of newer therapies for the treatment of myeloma. This started years ago with the discovery that Thalidomide, was extremely effective for the treatment of myeloma. Soon, more of these so-called novel therapies were developed, leading to a significant increase in the survival of patients who have access to these drugs.

The latest and most impressive of these treatments are certainly the development of monoclonal antibodies and CAR-T cells, both of which are extremely effective even in high risk or resistant myeloma. There is so much excitement about all the newer therapies, but access remains a challenge in theSouth African market.

A strong collaborative effort is required amongst pharmaceutical companies, government and medical schemes, to improve the current access of newer drugs. Nevertheless, some of these drugs have been around for many years and the costs have come down considerably, making it accessible to more people.

The initial treatment of myeloma generally consists of varying combinations of these drugs depending on the patients age, physical condition and of course, the available funding.

We usually use 3 different drugs in combination (a so-called triplet regimen) which has been proven to be very effective. Once the treatment is started, we take blood regularly to monitor the abnormal antibody levels in the blood which, as mentioned earlier, is a surrogate indicator of the number of cancer cells remaining in the bone marrow.

If we dont see a significant downward trend, the disease is likely resistant to that specific treatment combination and treatment should be adjusted accordingly. However, if the antibody levels come down significantly, we are on the right track and can continue with the same treatment until an optimal response is obtained or the development of side-effects forces us to make an adjustment.

After 4-6 months of treatment, the hope is to see no sign of any abnormal antibodies or cancer cells anymore (we call this a remission), or at least a dramatic reduction. We do however know that although we sometimes dont pick up any sign of residual disease, it is merely because the available tests are not sensitive enough. There will always be some cancer cells that remain.

As a general principle, however, the less residual disease, the longer it usually takes before it causes problems again. Because of this, we usually treat younger patients more aggressively in an attempt to obtain a deeper remission. The biggest difference in younger patients is the use of an autologous stem cell transplant as a 2nd phase of treatment to try and obtain or deepen a remission.

We harvest the patients bone marrow stem cells and keep them frozen until needed. We then administer a single high dose chemotherapy which destroys many of the remaining cancer cells, but in the process, it also destroys the normal bone marrow, without which you cannot survive. The patients stem cells are then thawed and given back to them like a blood transfusion.

After about two weeks of close monitoring in the hospital, the stem cells start to function and the patient subsequently has his/her own bone marrow back, hopefully with significantly less myeloma. The age cut-off for such a procedure is arbitrary because it largely depends on the physical condition of the patient. Most people in South Africa, however, use the age of 70 as a cut off, sometimes a bit older if the patient is in exceptional condition for his/her age.

The median age of people diagnosed with myeloma worldwide is about 70 years. The available data, however, suggests that the median age in South Africa is considerably younger, somewhere around the age of 60 years. Due to this, as well as the problems with drug availability in South Africa, we often rely quite heavily on stem cell transplantation as an important part of treatment. If enough stem cells are harvested and cryopreserved, such a transplant can be repeated on numerous occasions to improve disease control.

After a transplant, as well as for those patients who are not candidates for a transplant, a form of low-intensity maintenance therapy is often started as the next phase of treatment in an attempt to keep the disease under control for as long as possible. This duration varies considerably. We hope for a couple of years, but it is unfortunately sometimes just a couple of months before the disease worsens, after which more intense treatment needs to be restarted again and the above cycle repeats itself. The remission duration gives us a good indication regarding the nature and prognosis of the disease.

There is so much more detail about myeloma to share, but the bottom line is this: Although myeloma is not a curable cancer and can lead to devastating complications, there is good treatment available which can help many patients enjoy a good quality of life for many years.

It is important to diagnose myeloma early, so if you have some of the symptoms mentioned earlier, please contact your General Practitioner for further investigation. If any abnormalities are detected, your GP can refer you to aClinical Haematologist, who specialises in bone marrow cancers and are best equipped to treat your myeloma.

We are all very excited about the future of myeloma treatment and hope that the treating physicians, pharmaceutical companies and government can take hands to ensure proper treatment for all the people in South Africa who suffer from this disease.

This article was compiled by Dr. Hannes Koornhof (Chairman of SACHAS)MBChB, FCP (SA), Dip HIV Man (SA), Cert Clin Haematology (SA) PhysSponsored by JANSSEN PHARMACEUTICA(PTY) LTD/(EDMS) BPK. (Reg. No./Regnr. 1980/011122/07); No 2, Medical Road, Halfway House, Midrand, 1685.www.janssen.com.

Medical Info Line: 0860 11 11 17. EM-27036

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Everything you need to know about Myeloma - IOL

After performing well on the stock market last year -- with shares climbing by 37.3% -- Incyte's (NASDAQ:INCY) stock is down by 11% year to date. And while it would be easy to attribute this poor performance to the COVID-19 epidemic -- which has now spread to more than 50 countries and is hurting the stock market -- the fact is, Incyte's struggles predate these developments.In early January, before most of us had even heard of the coronavirus, Incyte's shares dropped by about 12% after the company reported disappointing results from a pivotal phase 3 clinical trial.

The clinical trial investigated the efficacy of itacitinib and corticosteroids as a combination treatment for treatment-naive acute graft-versus-host disease (GVHD), a condition that can develop in a patient following a stem cell transplant. The treatment failed to meet its primary or secondary endpoints. Despite this setback, Incyte has a plan to get back on the right track, and here are two things that could help the company do just that.

Image source: Getty Images.

Incyte's top selling-product is Jakafi, which treats several conditions, including a rare bone marrow cancer called myelofibrosis. Jakafi also treats patients with polycythemia vera, a condition that leads to an abnormal increase in the production of red blood cells.Lastly, in May 2019, the U.S. Food and Drug Administration (FDA) approved Jakafi for the treatment of steroid-refractory acute GVHD, a condition that occurs when a patient receives a stem cell transplant and the donor's cells trigger an immune response and attack the recipient's organs.Incidences of this condition number about 5,700 cases a year.

Also, steroid-refractory acute GVHD has a one-year mortality rate of about 70%.Jakafi is the first and only FDA-approved treatment for steroid-refractory acute GVHD. Thanks to this relatively new indication, sales of Jakafi could continue growing, as they have been doing for the past few years. During the fourth quarter, Jakafi's net product revenue was $466.5 million, 23% higher than the year-ago period. For the full year, Jakafi's net product revenue was $1.7 billion, a 21% increase compared to 2018.According to Incyte's executive vice president, Barry P. Flannelly, "Patient demand continued to drive the uptake of Jakafi and growth was strong across all three indications."

Furthermore, Incyte collects royalty revenues from Novartis (NYSE:NVS), which holds the rights to Jakafi outside the U.S. Incyte's royalty revenue for Jakafi for the fourth quarter and the full year were $65 million and $225.9 million, respectively, which represented an increase of 17% for the fourth quarter and 16% for the full year.

According to Incyte, Jakafi has been growing its revenue at a compound annual growth rate of 29% since 2016. And the company hopes its crown jewel will continue performing well in the future. Incyte's CEO Herve Hoppenot said, "On the commercial side, we will work to drive continued Jakafi growth in all three indications."

While Jakafi is performing well, Incyte does rely heavily on this product. During the fourth quarter, Jakafi's net product revenue accounted for about 80.5% of the company's total revenue. Fortunately, Incyte is trying to decrease its top-line exposure to its top-selling drug. In February, Incyte submitted capmatinib to the FDA as a potential treatment for an aggressive type of non-small cell lung cancer (NSCLC) called metastatic MET exon 14 skipping (METex14) mutated NSCLC.

There are currently no approved therapies that specifically target this type of NSCLC, which occurs in 3% to 4% of advanced NSCLC cases. Lung cancer is the most common type of cancer in the world, and NSCLC is the most common form of lung cancer. The FDA granted capmatinib a priority review designation, which means the review process for this drug will go faster than usual.

Also, in November 2019, Incyte submitted a New Drug Application to the FDA for pemigatinib as a potential treatment for cholangiocarcinoma, a rare cancer that affects about 0.3 to 3.4 per 100,000 people in North America and Europe. The FDA also granted pemigatinib priority review.In addition to those products that are currently being reviewed by regulatory authorities, Incyte boasts several more pipeline candidates for a variety of other conditions.This could help the company become less reliant on Jakafi in the future.

Incyte's heavy reliance on Jakafi remains a concern, and for that reason, Incyte probably isn't a strong buy. However, Jakafi's revenue should continue climbing, and unless Incyte runs into regulatory roadblocks, it should have several more products to drive its sales even higher. In short, investors should keep an eye on this biotech company.

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These 2 Things Will Help Incytes Stock Rebound - Motley Fool

The latest Stem Cell Therapy market study offers an all-inclusive analysis of the major strategies, corporate models, and market shares of the most noticeable players in this market. The study offers a thorough analysis of the key persuading factors, market figures in terms of revenues, segmental data, regional data, and country-wise data. This study can be described as most wide-ranging documentation that comprises all the aspects of the evolving Stem Cell Therapy market.

The research report provides deep insights into the global market revenue, parent market trends, macro-economic indicators, and governing factors, along with market attractiveness per market segment. The report provides an overview of the growth rate of Stem Cell Therapy market during the forecast period, i.e., 20202027. Most importantly, the report further identifies the qualitative impact of various market factors on market segments and geographies. The research segments the market on the basis of product type, application, technology, and region. To offer more clarity regarding the industry, the report takes a closer look at the current status of various factors including but not limited to supply chain management, niche markets, distribution channel, trade, supply, and demand and production capability across different countries.

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Stem cell therapy is a technique which uses stem cells for the treatment of various disorders. Stem cell therapy is capable of curing broad spectrum of disorders ranging from simple to life threatening. These stem cells are obtained from different sources, such as, adipose tissue, bone marrow, embryonic stem cell and cord blood among others. Stem cell therapy is enables to treat more than 70 disorders, including degenerative as well as neuromuscular disorders. The ability of a stem cell to renew itself helps in replacing the damaged areas in the human body.

MARKET DYNAMICSIncrease in the number of stem cell banking facilities and rising awareness on the benefits of stem cell for curing various disorders are expected to drive the market during the forecast period. Rise in number of regulations to promote stem cell therapy and increase in number of funds for research in developing countries are expected to offer growth opportunities to the market during the coming years.

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The research provides answers to the following key questions:

The study conducts SWOT analysis to evaluate strengths and weaknesses of the key players in the Stem Cell Therapy market. Further, the report conducts an intricate examination of drivers and restraints operating in the market. The report also evaluates the trends observed in the parent market, along with the macro-economic indicators, prevailing factors, and market appeal according to different segments. The report also predicts the influence of different industry aspects on the Stem Cell Therapy market segments and regions.

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Stem Cell Therapy Market Segmented by Region/Country: North America, Europe, Asia Pacific, Middle East & Africa, and Central & South America

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The Insight Partners is a one stop industry research provider of actionable intelligence. We help our clients in getting solutions to their research requirements through our syndicated and consulting research services. We are committed to provide highest quality research and consulting services to our customers. We help our clients understand the key market trends, identify opportunities, and make informed decisions with our market research offerings at an affordable cost.

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Stem Cell Therapy Market 2020 To 2027-Expanding Worldwide with Top Players Future Business Scope and Investment Analysis Report - Monroe Scoop

Results Surpass FDA-Agreed Efficacy Threshold

Omeros Corporation (Nasdaq: OMER) today reports an update on clinical data from its pivotal trial of narsoplimab in the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), markedly exceeding the FDA-agreed threshold for the primary efficacy endpoint. While an overview of preliminary data submitted to FDA was made public on December 4, 2019 in a press release from the company, all patients have now completed treatment and trial enrollment has been closed. Narsoplimab is Omeros human monoclonal antibody targeting mannan-binding lectin-associated serine protease 2 (MASP-2).

In recent meetings with FDA focused on clinical as well as chemistry, manufacturing and controls (CMC) data, FDA confirmed important aspects of Omeros rolling Biologics License Application (BLA) for narsoplimab in HSCT-TMA. The BLA continues on its clear path to completion.

The efficacy threshold agreed with FDA, the updated results from the 28-patient trial, and highlights of the recent FDA meetings are the following:

Primary Endpoint

Secondary Endpoints

Safety

The treated population had multiple high-risk features that portend a poor outcome, including the persistence of HSCT-TMA despite modification of immunosuppression (which was a criterion for entry into the trial), graft-versus-host disease, significant infections, non-infectious pulmonary complications and neurological findings. Patients in the trial had a high expected mortality rate, with 93% of them having multiple risk factors.

"The efficacy and safety data from the pivotal trial with narsoplimab are encouraging," said Miguel-Angel Perales, M.D., Deputy Chief of the Adult Bone Marrow Transplantation Service and Director of the Adult Stem Cell Transplantation Fellowship at Memorial Sloan Kettering Cancer Center. "Given the trials stringent response criteria across laboratory markers and organ function, the complete response rate seen with narsoplimab is remarkable, as is the 100-day survival. There currently is no approved treatment for HSCT-TMA. Current therapy is generally limited to supportive care and withdrawal of drugs critical for GVHD prophylaxis. Not only could narsoplimab become central to the treatment of HSCT-TMA, it might well allow us to maintain that needed GVHD prophylaxis."

Complete clinical trial data will be presented by Dr. Perales later this month at the Annual Meeting of the European Society for Blood and Marrow Transplantation in Madrid.

Recent FDA Meeting Highlights and CMC Updates

"The non clinical sections of our BLA have been submitted, our CMC campaign is progressing well with process validation and commercial lots already manufactured, and our pivotal trial is complete," stated Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros. "The efficacy threshold agreed with FDA reflects both the primary endpoints stringent response criteria and the poor outcomes expected in the patients enrolled in our trial. Of course, were very pleased that the response rates and confidence intervals seen with narsoplimab are well above that efficacy threshold. We look forward to continuing to work closely with regulators to make the drug commercially available to transplanters and their patients in the U.S. and internationally as quickly as possible."

In addition to its HSCT-TMA program, Omeros is enrolling its narsoplimab Phase 3 clinical trials for immunoglobulin A (IgA) nephropathy and atypical hemolytic uremic syndrome (aHUS). Narsoplimab has been granted, for both HSCT-TMA and IgA nephropathy, FDAs breakthrough therapy designation as well as orphan drug designations from FDA and the European Medicines Agency. The drug also holds FDAs fast-track designation for aHUS.

Primary Efficacy Endpoint

To be considered a responder, a patient must achieve the primary endpoint of complete HSCT-TMA response defined by improvement in laboratory markers and improvement in clinical status.

Laboratory Markers

Clinical Status

About Omeros Corporation

Omeros is an innovative biopharmaceutical company committed to discovering, developing and commercializing small-molecule and protein therapeutics for large-market as well as orphan indications targeting complement-mediated diseases, disorders of the central nervous system and immune-related diseases, including cancers. In addition to its commercial product OMIDRIA (phenylephrine and ketorolac intraocular solution) 1%/0.3%, Omeros has multiple Phase 3 and Phase 2 clinical-stage development programs focused on complement-mediated disorders and substance abuse. In addition, the company has a diverse group of preclinical programs including GPR174, a novel target in immuno-oncology that modulates a new cancer immunity axis recently discovered by Omeros. Small-molecule inhibitors of GPR174 are part of Omeros proprietary G protein-coupled receptor (GPCR) platform through which it controls 54 new GPCR drug targets and their corresponding compounds. The company also exclusively possesses a novel antibody-generating platform.

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About HSCT-TMA

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a significant and often lethal complication of stem cell transplants. This condition is a systemic, multifactorial disorder caused by endothelial cell damage induced by conditioning regimens, immunosuppressant therapies, infection, GvHD, and other factors associated with stem cell transplantation. Endothelial damage, which activates the lectin pathway of complement, plays a central role in the development of HSCT-TMA. The condition occurs in both autologous and allogeneic transplants but is more common in the allogeneic population. In the United States and Europe, approximately 25,000 to 30,000 allogeneic transplants are performed annually. Recent reports in both adult and pediatric allogeneic stem cell transplant populations have found an HSCT-TMA incidence of approximately 40 percent, and high-risk features may be present in up to 80 percent of these patients. In severe cases of HSCT-TMA, mortality can exceed 90 percent and, even in those who survive, long-term renal sequalae are common. There is no approved therapy or standard of care for HSCT-TMA.

About Narsoplimab

Narsoplimab, also known as "OMS721," is an investigational human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a novel pro-inflammatory protein target and the effector enzyme of the lectin pathway of complement. Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. Omeros controls the worldwide rights to MASP-2 and all therapeutics targeting MASP-2.

Phase 3 clinical programs are in progress for narsoplimab in hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), in immunoglobulin A (IgA) nephropathy, and in atypical hemolytic uremic syndrome (aHUS). The FDA has granted narsoplimab breakthrough therapy designations for HSCT-TMA and for IgA nephropathy; orphan drug status for the prevention (inhibition) of complement-mediated thrombotic microangiopathies, for the treatment of HSCT-TMA and for the treatment of IgA nephropathy; and fast track designation for the treatment of patients with aHUS. The European Medicines Agency has granted orphan drug designation to narsoplimab for treatment in HSCT and for treatment of primary IgA nephropathy.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, which are subject to the "safe harbor" created by those sections for such statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "can," "could," "estimate," "expect," "goal," "intend," "likely", "look forward to," "may," "on track," "plan," "potential," "predict," "project," "prospects," "scheduled," "should," "slated," "targeting," "will," "would" and similar expressions and variations thereof. Forward-looking statements, including statements regarding anticipated regulatory submissions, expectations regarding regulatory exclusivities, the timing and results of ongoing or anticipated clinical trials, and the therapeutic application of Omeros investigational product, are based on managements beliefs and assumptions and on information available to management only as of the date of this press release. Omeros actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, availability and timing of data from clinical trials and the results of such trials, unproven preclinical and clinical development activities, regulatory oversight, intellectual property claims, competitive developments, litigation, and the risks, uncertainties and other factors described under the heading "Risk Factors" in the companys Annual Report on Form 10-K for the year ended December 31, 2019, filed with the Securities and Exchange Commission on March 2, 2020. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and the company assumes no obligation to update these forward-looking statements, whether as a result of any new information, future events or otherwise, except as required by applicable law.

Dr. Miguel-Angel Perales has received compensation from Omeros for advisory services.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200302005938/en/

Contacts

Jennifer Cook WilliamsCook Williams Communications, Inc.Investor and Media Relations360.668.3701jennifer@cwcomm.org

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Omeros Corporation Reports Updated Results from Narsoplimab HSCT-TMA Clinical Trial and Highlights from Recent Clinical and CMC Meetings with FDA -...

Why is it that when a woman runs for an office or does something remarkable so very often the first thing people say is look at her hair or WHAT is she wearing! Well, there is a woman whose photos adorn the halls of the volunteer organization where I volunteer. And because she is the founder of the organization there are lots of photos in the office and in books about the history of the organization. The organization is Hadassah, The Womens Zionist Organization of America. The woman, the founder, is Henrietta Szold (1860-1945).

When I look at her photos, I dont focus on her hair, which changed little over the decades of her work. I dont look at the black pocketbook she often carried which seems not to have changed over the decades of her work. I dont think about her shoes, which were sturdy and usually black. Nope when I look at Miss Henrietta Szolds photo the first thing I think of look at how strong she is, look at the determination and purpose in her eyes, look at what those eyes have seen and those hands have touched. The rest unimportant and anecdotal.

As we are commemorating Womens History and Womens Empowerment Month in March, its very appropriate to tell you that even before Henrietta started Hadassah in a New York City synagogue in 1912 with a study group, she had, in her young life, already broken gender barriers and established institutions. Henrietta started the first night school for immigrants in the US and she studied at the Jewish Theological Seminary in an era when the idea of a female rabbi was unthinkable. An empowered woman look no further absolutely.

When Henriettas eyes first saw the disease and living conditions of the Jews in pre-state Israel on a trip with her mother in 1911, her mission of practical Zionism and her purpose were born. When you read her letters looking for funding or in subsequent years, letters between her and the nurses she sent over to provide pasteurized milk to babies and new moms, and to set up public health stations in Jerusalem to fight off the flies on the eyes of children suffering from trachoma, her words are full of determination and, excuse the old fashioned word gumption. This woman had moxie, this woman had chutzpah, this woman had guts. And thank G-d she did. Because she and her womens organization built the State of Israel. Hadassah created the medical infrastructure of Palestine and continues to do so today in Israel, a mere 108 years later. When there is purpose to what you are committed to and that purpose is accompanied by action there can be longevity. How about an organization that looks forward to the next 100 years? How about volunteers that are active for decades?

They say the proof is in the pudding, that you can judge something only once you have used or experienced it. So: Been there. Done that. Doing it.

Ive been a life member of Hadassah for 54 years, worked in just about every capacity and position at every possible level of the organization. I have gone to Israel so many times but when I juxtapose the memories of my first visit in 1966 with my most recent visit in 2018, WOW, the differences are staggering. Close to the top of the list are the ongoing changes at Hadassah Hospitals and Youth Villages. In the early years, beginning in 1913 when Henrietta sent over the first two nurses, Hadassah Hospitals and Clinics covered the map and over the years. Hadassah and the Hadassah Medical Organization (HMO) created many firsts the first medical school, dental school, nursing school, cancer institute, childrens hospice, ambulatory surgery center, ER unit for premature babies, and trauma treatment center in Israel.

Today the two hills of healing stand at opposite ends of Jerusalem Mt. Scopus (opened in 1939, closed in 1948, reopened in 1975) and the Ein Kerem campus, a tertiary care facility, built in 1961 as Ben Gurion told Hadassah to build in the southwest outskirts of Jerusalem and the city would grow out to it. Which is just what happened. Today, a light rail and bus bring people from all over the area to the hospital. In 2012, the Sarah Wetsman Davidson Hospital Tower opened adding 500 beds and 20 operating theaters. In 2020, Hadassah is re-imagining and re-energizing the campus with its 360 Degrees of Healing Campaign.

Hadassah Hospitals were first in Israel with heart, liver, lung and bone marrow transplants, computer-guided hip replacement (first in the world), macular degeneration clinical trial using embryonic stem cells to repair vision (second in the world) and bone marrow registry for Arabs (only one in the world). Hadassah Medical Organization (HMO) triage procedures and surgical techniques developed by Hadassah doctors were used following the Boston Marathon bombing. HMO doctors and nurses have been first responders in the Philippines, Haiti, Indonesia and Thailand in the wake of natural disasters. Hadassah doctors recently brought humanitarian spinal surgery to Ethiopia.

No rest for this woman she found more purpose and then, more purpose, as time went on.

As a 70-year-old woman, Henrietta was a member of the Palestine Zionist Executive, the Jewish Agency Executive and the Vaad Leumi. Photos show her as often being the only woman in the room. In these capacities she directed the health/educational development and social services of the population. And then, Henrietta took over the daily operations of Youth Aliyah in Palestine. Youth Aliyah was created to bring Jewish children out of Nazi Germany and bring them to Palestine.

In 1943, Henrietta waited in the cold at the Atlit Detention Camp as 750 children from Iran disembarked a train (120 followed a few months later), saved from the atrocities of Nazi Germany. Hadassah joined the life-saving work of Youth Aliyah and continues to be a major supporter to this day. Today, Hadassah-supported youth villages, Meir Shfeyah, Ramat Hadassah Szold and Hadassah Neurim, set at-risk children in Israel on the road to success and since its beginning, more than 300,000 young people from 80 lands have graduated from Youth Aliyah.

Always with an eye to the future, Henrietta Szolds connection to Young Judaea, began in 1909, when she prompted the Federation of American Zionists to call for a junior Zionist convention of delegates from Zionist youth societies. Young Judaea was formally established as a national Zionist youth organization at that New York convention. And then, under the leadership of Henrietta Szold, the department of education was formed by the Zionist Organization of America (ZOA), which briefly sponsored Young Judaea from 1918 to 1921. Over the years, there were many different connections between Henrietta, Hadassah and Young Judaea. Today, Hadassah and Young Judaea continue their connection through their shared mission to forge a strong commitment to Jewish life, instill a love of Israel and Zionism, connect American kids to Israel through education and programs, develop leaders for the Jewish community, and advocacy. Henrietta Szold and Hadassah in the room!

Today Hadassah has 300,000 members, Associates and supporters. It is the largest Jewish womens membership organization in the United States. With members in every Congressional district, Hadassahs advocacy work in spear-heading important legislation, most recently, the Never Again Education Act working to ensure Holocaust education in public schools, is a direct modern-day application of Henriettas legacy and an illustration of purpose with action. Hadassah women are in the room!

So, I think you can see that Henrietta started a run a run of practical Zionism that stretches across decades and centuries. A run I am proud to be part of since it has enabled me to work for Israel while living here in New York. It has allowed me to make differences around the world through medical research and protocols that are shared. Four generations of life members in my family. Three generations of Hadassah Presidents in my family. Once I make our new grandson an Associate, five generations of men affiliated with Hadassah. For me, personally, Hadassah is a family affair.

Today Hadassah strives to empower women of all ages to make a difference and to become leaders in the Jewish community by continuing Henriettas legacy of Practical Zionism through our work in Israel, our advocacy here in the US, on issues that affect Israel, the Jewishcommunity and health. Henrietta asked the artist of her sculpture to make my eyes look to the future. A most meaningful and purposeful statement.

Boy, I would love to know what Henrietta carried in that black bag of hers, or better yet, what her bag would hold today. I can only imagine that shewasthe one with the tissues to wipe the eyes of the young children as they disembarked the train. Shewould bethe one with the cell phone to reach out to anyone who would listen to her pleas for assistance and for funding to facilitate medical research and care of youth. Shewould bethe one with the small flashlight to bring a big light unto the nations. Over the years I have implored our members to release their inner Henrietta. A woman of purpose and perseverance to emulate for sure.

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A Woman of Purpose and Perseverance - Thrive Global

DUBLIN, Feb. 27, 2020 /PRNewswire/ -- The "Stem Cell Banking - Market Analysis, Trends, and Forecasts" report has been added to ResearchAndMarkets.com's offering.

The growing interest in regenerative medicine which involves replacing, engineering or regenerating human cells, tissues or organs, will drive market growth of stem cells. Developments in stem cells bioprocessing are important and will be a key factor that will influence and help regenerative medicine research move into real-world clinical use. The impact of regenerative medicine on healthcare will be comparable to the impact of antibiotics, vaccines, and monoclonal antibodies in current clinical care. With the global regenerative medicine market poised to reach over US$45 billion by 2025, demand for stem cells will witness robust growth.

Another emerging application area for stem cells is in drug testing in the pharmaceutical field. New drugs in development can be safely, accurately, and effectively be tested on stem cells before commencing tests on animal and human models. Among the various types of stem cells, umbilical cord stem cells are growing in popularity as they are easy and safe to extract. After birth blood from the umbilical cord is extracted without posing risk either to the mother or the child. As compared to embryonic and fetal stem cells which are saddled with safety and ethical issues, umbilical cord is recovered postnatally and is today an inexpensive and valuable source of multipotent stem cells. Until now discarded as waste material, umbilical cord blood is today acknowledged as a valuable source of blood stem cells. The huge gap between newborns and available cord blood banks reveals huge untapped opportunity for developing and establishing a more effective banking system for making this type of stem cells viable for commercial scale production and supply. Umbilical cord and placenta contain haematopoietic blood stem cells (HSCs). These are the only cells capable of producing immune system cells (red cells, white cells and platelet).

HSCs are valuable in the treatment of blood diseases and successful bone marrow transplants. Also, unlike bone marrow stem cells, umbilical cord blood has the advantage of having 'off-the-shelf' uses as it requires no human leukocyte antigen (HLA) tissue matching. Developments in stem cell preservation will remain crucial for successful stem cell banking. Among the preservation technologies, cryopreservation remains popular. Development of additives for protecting cells from the stresses of freezing and thawing will also be important for the future of the market. The United States and Europe represent large markets worldwide with a combined share of 60.5% of the market. China ranks as the fastest growing market with a CAGR of 10.8% over the analysis period supported by the large and growing network of umbilical cord blood banks in the country. The Chinese government has, over the years, systematically nurtured the growth of umbilical cord blood (UCB) banks under the 'Developmental and Reproductive Research Initiation' program launched in 2008. Several hybrid public-private partnerships and favorable governmental licensing policies today are responsible for the current growth in this market.

Competitors identified in this market include:

Companies Mentioned

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Global Stem Cell Market Poised for Strong Growth as Global Regenerative Medicine Market Poised to Reach US$45 billion by 2025 - P&T Community

A bone marrow donor registry drive on Texas A&M Universitys campus brought more than 400 students to Duncan Dining Hall on Friday.

Participants swabbed their mouths to provide DNA samples and have their names added to Be the Matchs national bone marrow registry, which will help people in need of bone marrow connect with donors. The event was a collaborative effort between the A&M Corps of Cadets, the Kidz1stFund and Be the Match.

If anyone is matched, Community Engagement Representative for Be the Match Gulf Coast Benita Davis said they will need to have additional blood work done before donating.

A&M senior and Cadet 1st Lt. Mitchell Moore said his attendance on Friday was motivated in part by his interest in the medical field, since he is aiming to go to medical school.

Its minimum to no risk for you and not too much time, Moore said about donating. A small time on your part can make a huge difference and extend someones life by years.

A&M football coach Jimbo Fisher and Candi Fisher started Kidz1stFund in 2011 to raise money for research about fanconi anemia, which is a rare blood disorder that their teenage son was diagnosed with. Fisher stopped by Fridays event to speak with organizers and meet participants.

Its amazing how many great people there are in this world who are willing to help other people, Fisher said. These young men and women out here are actually saving lives.

Davis said donating is not as painful as many people often think, especially since about 80% of donations can be made with the nonsurgical method of giving peripheral blood stem cells. The other 20% of donations involve marrow being removed from the hip while the donor is asleep under general anesthesia. According to the Be the Match website, about one in 430 people on the registry end up donating.

The cadets in attendance on Friday were a reflection of who they are as people and students, according to Amy Thompson, assistant commandant, marketing and communications for the Corps of Cadets.

Selfless service is an A&M core value its also a core value for the Corps of Cadets, Thompson said. The commandant really supports and encourages cadets to seek out opportunities to be leaders in selfless service. This is one of those opportunities where we can do that on a very large scale and make a huge impact.

Corps Squadron 1 commander and A&M senior Jacob Svetz donated using stem cells about two years ago. He said he thinks everyone should sign up for the registry.

The few pin pricks that you get Its such a miniscule amount of pain compared to what that family and individual are suffering through, Svetz said. To put yourself into a position to be able to help that for me, it doesnt make sense not to.

Be the Match On Campus President and A&M senior Paige Boone said the organization hosts drives every month. The next one will be March 25 at A&Ms Rudder Plaza. Home swab kits are also an option. To get started, visit join.bethematch.org or text CORPS to 61474. Anyone ages 18 to 44 can participate.

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Jimbo Fisher's Kidz1stFund, Aggie Corps of Cadets team up for Be the Match bone marrow donor registry drive - Bryan-College Station Eagle

The bag that Laurie Olesen gripped as she walked through the airport looked like any other carry-on. But the bright blue canvas tote would carry more than her cellphone, e-reader and toiletries. It would hold the last, best hope of survival for a desperately ill patient.

Bound for the East Coast, Olesen was on a mission to pick up blood stem cells or bone marrow provided by a donor, then fly with it to another city where it would be transfused into a recipient.

The product travels so the patient or the donor doesnt have to, said Olesen, 66, of St. Paul.

Olesen is a volunteer courier for Be The Match. Based in Minneapolis, the nonprofit registry serves people diagnosed with a variety of life-threatening blood, bone marrow or immune system disorders.

Shes one of a cadre of 400 of specially trained volunteers that form a crucial, reliable and affordable link between donors and patients.

These couriers are prepared to get a call, race to the airport and reach across time zones with a perishable product that comes with a true deadline. The consequences of a delay can be devastating even lethal for a patient waiting for the unique match.

Our volunteer couriers have to work on a tight time frame. They manage the paperwork and fill out a chain of custody form to document exactly where the cooler has been. We want it in a volunteers line of sight at all times, said Rut Kessel, volunteer specialist with Be The Match. They protect it with their life because it is a life.

Only about 30% of patients who need a bone marrow or blood stem cell transplant can find a donor within their family. Be The Match provides an international database of more than 20 million to locate an unrelated donor. When such a wide net is cast, the recipient and the anonymous donor rarely live in the same city. Theyre usually in different states, regions or even countries.

Thats where couriers come in.

Many volunteers are retirees who have time and flexibility. The gig also attracts firefighters, health care workers and airline employees whose shift work creates consistent open days in their schedules. While costs for their flights, hotels and other travel expenses are covered, couriers arent paid for their time.

They also never meet or even learn the names of donors or recipients. They typically pick up a numbered product at one lab and deliver it to another.

We have strict rules about confidentiality, explained Kessel. The courier experience is detached from the people involved. Something has gone terribly wrong if a courier ever meets or even sees a donor or recipient.

But many couriers have a personal connection to Be The Match.

Someone did this for me, said Lisa Maxson, 37, an Ohioan who was diagnosed with acute myeloid leukemia in 2011. Hospitalized for months while she had chemotherapy and radiation to kill her own diseased bone marrow, the mother of three underwent a transplant to replace it with healthy donor cells.

While I was sick, I decided I would give back to the organization that saved my life, she said.

Her family now sponsors a 5K race to benefit Be The Match. And this winter, she traveled to the registrys headquarters in the North Loop to take the two-day training for volunteer couriers.

Im so excited to be a courier for my transplant brothers and sisters, she said. I know what it feels like to be afraid youre going to die.

The gift of life

Every day of the year, volunteer couriers are in the air, crisscrossing the globe with the lifesaving cargo in temperature-controlled, medical coolers tucked under their seats. Last year, couriers living in 15 America cities made more than 2,600 trips, about a quarter of them to international destinations.

Five Minneapolis-based travel agents book their flights and manage their itineraries. Like the couriers themselves, the travel agents have to be nimble and act quickly when the unexpected occurs. Theyre also on call round-the-clock to rebook trips if mechanical difficulties cancel a flight or blizzards or hurricanes snag the travel grid, said Bonnie Bagley, who supervises the agents.

Two years ago, Bagley became a volunteer courier and now uses vacation time to make deliveries.

That closed the loop for me. Now I literally see how the system that Ive had a glimpse of works for patients, she said. I understand the passion our volunteers have. Theres an adrenaline rush when youre carrying the product.

For her part, Olesen likely holds the record for the most trips, which she estimates at a hundred deliveries to every region in the United States as well as a number of foreign countries.

Couriers have to be assertive, but must also remain calm, she said. You cant get rattled when things dont go as planned.

Shes also learned how best to deal with foreign customs agents.

When you bring a product from another country into the U.S., you have to declare the product to customs. You carry a special letter but, to tell the truth, some agents dont know what theyre supposed to do. Thats where the diplomacy comes in, said Olesen. You have to help them do their job without alienating or provoking them. You learn to kill them with kindness.

In 1986, Olesen was the first employee for the organization that became Be The Match. A registered nurse, she was working with blood collection at the American Red Cross in St. Paul when it was among a consortium of blood banks that received a grant to develop the nations first bone marrow registry. She was hired to identify donors for specific patients.

She joined the few lab technicians and transplant center employees who flew donations from donor to recipient. As the registry expanded and number of patients and donors increased, Be The Match added volunteer couriers in 2004. Olesen set up volunteer and education programs, managed search operations and kept up her courier duties.

While most of her deliveries have gone off without a hitch, shes had a few near-misses, including the time when a drop-off spot in Barcelona turned out to be a dead end. She and a cabdriver bridged their language gap to figure out the correct spot and hustle across the city.

We have guidelines for tipping, but that was one time I gave a little extra out of my own pocket, Olesen recalled. He went above and beyond.

And then there was the time when she had completed her pickup in London, only to arrive at the airport as a snowstorm shut it down.

I went to the gate agent and told them I was carrying bone marrow. They declared the flight a life flight and our plane was prioritized. We took off when the first runway opened, she said. When you do this, the courier gods are always on your side.

Although Olesen retired from Be The Match two years ago, she keeps her bag packed and her passport ready so she can continue to fly as a volunteer.

Being a courier reminds me of what were about. It affirms why we do what we do every day, she said. I know that within 24 hours after I get the product to its destination, it will be transfused into the recipient. That can give a person their life back.

Kevyn Burger is a Minneapolis-based freelance broadcaster and writer.

Originally posted here:
Carry-on item for Be the Match volunteers: Organ transplants - Minneapolis Star Tribune

CHICAGO About 54 million Americans suffer from the aches and pains of arthritis.

Treatments range from pain medications to injections to surgery.

None of it seemed to work for 77-year-old Marty Ciesielczyk.

And it jeopardized something he loved: jogging.

"For me, it's just enjoyable, and if you're not a runner, then you would have no idea what I'm talking about."

But Marty's active lifestyle was in jeopardy when knee pain took over.

"When you got to lay on the floor to get dressed, it's tough."

It happens when there's a loss of cartilage in the joint.

"It's like a tire, and as you slowly lose rubber on the tire, it wears away," explained Dr. Adam Yanke, a surgeon with Midwest Orthopaedics at Rush University.

"You might need to have the tire replaced at some point."

Marty's arthritis was too advanced for a scope procedure but not bad enough for a joint replacement.

So he enrolled in a study testing whether amniotic fluid, which surrounds a growing baby in the uterus, could help his pain.

"Amniotic products come from patients that are having healthy, elective C-sections, and they choose to donate these products at the time of the delivery," said Dr. Yanke.

It's thought to increase tissue healing and lower inflammation.

Doctor-diagnosed arthritisis more common in womenthan in men. Arthritis and other joint disorders are among the five most costly conditions among adults 18 and older.

Your bone marrow makes mesenchymal stem cells, or MSCs. They are known to grow into new tissues, including cartilage.

By gathering these cells and injecting them into the knee joint, the hope is that they will give growth to new cartilage and reduce inflammation.

Marty received a placebo during the study, but then chose to have the amniotic fluid when the study ended.

"I mean I didn't care if it was Pixie dust, as long as my knee was going to feel better."

He went from not being able to get dressed to jogging about a week after having the injection.

"This morning, I ran three, three miles, and I had no problem at all."

Amniotic fluid is also being used to treat ulcers in the eye.

Rush University will be enrolling patients for a larger follow-up study on amniotic fluid for joint pain in the future.

Clinical trialsare still going on and most studies are still early.

A review published in 2016 in BMC Musculoskeletal Disorders concluded that MSC-based therapies offer an "exciting possibility" for treatment, but further studies need to be done on how they can best be used and how well they work.

They are also known to be very expensive.

If this story has impacted your life or prompted you or someone you know to seek or change treatments, please let us know by contacting Jim Mertens atjim.mertens@wqad.comor Marjorie Bekaert Thomas atmthomas@ivanhoe.com.

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YOUR HEALTH: Knee relief can be found in the womb - WQAD.com

TEL AVIV, Israel, Feb. 27, 2020 /PRNewswire/ -- BioLineRx Ltd. (NASDAQ: BLRX), (TASE: BLRX), a late clinical-stage biopharmaceutical company focused on oncology, announced today that a Notice of Allowance has been issued by the United States Patent and Trademark Office (USPTO) for a patent application claiming the use of motixafortide (BL-8040), a novel immunotherapy compound, combined with any PD-1 inhibitor, for the treatment of any type of cancer.

The PD-1 antagonist can be any agent that prevents and/or inhibits the biological function and/or expression of PD-1, such as pembrolizumab (KEYTRUDA). The targeted cancer can be solid, non-solid, and/or a cancer metastasis.

This patent, whenmedi issued, will be valid until July 2036 with a possibility of up to five years patent term extension. Additional corresponding patent applications are pending in Europe, Japan, China, Canada, Australia, India, Korea, Mexico, Brazil and Israel.

"We are extremely pleased to receive this valuable notice of allowance from the USPTO, which entitles us to long-term, highly enforceable and broad patent protection for our lead product, motixafortide, in combination with any PD-1 inhibitor, and more importantly, for all cancer indications, including, of course, any solid tumor," stated Philip Serlin, Chief Executive Officer of BioLineRx. "This important patent allowance also supports our ongoing Phase 2a COMBAT/KEYNOTE-202, for which we have recently completed patient recruitment in the triple combination arm investigating the safety, tolerability and efficacy of motixafortide, KEYTRUDA and chemotherapy. Following promising initial results demonstrating robust and durable responses to the triple combination treatment, we look forward to the progression-free and overall survival data from the triple combination arm expected in mid-2020."

The COMBAT/KEYNOTE-202 Study

The Phase 2a COMBAT/KEYNOTE-202 study was originally designed as an open-label, multicenter, single-arm trial to evaluate the safety and efficacy of the dual combination of motixafortideand KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in over 30 subjects with metastatic pancreatic adenocarcinoma. The study was primarily designed to evaluate the clinical response, safety and tolerability of the combination of these therapies, and was carried out in the US, Israel and additional territories. The study is being conducted by BioLineRx under a collaboration agreement signed in 2016 between BioLineRx and MSD, through a subsidiary.

In July 2018, the Company announced the expansion of its immuno-oncology collaboration with MSD to include the triple combination arm investigating the safety, tolerability and efficacy of motixafortide, KEYTRUDA and chemotherapy as part of the Phase 2a COMBAT/KEYNOTE-202 study. In January 2020, the Company announced completion of recruitment of the 40 patients planned for the triple combination arm of the study.

About Motixafortide in Cancer Immunotherapy

Motixafortideis targeting CXCR4, a chemokine receptor and a well validated therapeutic target that is over-expressed in many human cancers including PDAC. CXCR4 plays a key role in tumor growth, invasion, angiogenesis, metastasis and therapeutic resistance, and CXCR4 overexpression has been shown to be correlated with poor prognosis.

Motixafortideis a short synthetic peptide used as a platform for cancer immunotherapy with unique features allowing it to function as a best-in-class antagonist of CXCR4. It shows high-affinity, long receptor occupancy and acts as an inverse agonist.

In a number of clinical and preclinical studies, motixafortidehas been shown to affect multiple modes of action in "cold" tumors, including immune cell trafficking, tumor infiltration by immune effector T cells, and reduction in immunosuppressive cells (such as MDSCs) within the tumor niche, turning "cold" tumors, such as pancreatic cancer, "hot" (i.e., sensitizing them to immune checkpoint inhibitors and chemotherapy).

About BioLineRx

BioLineRx Ltd. (NASDAQ: BLRX), (TASE: BLRX) is a clinical-stage biopharmaceutical company focused on oncology. The Company's business model is to in-license novel compounds, develop them through clinical stages, and then partner with pharmaceutical companies for further clinical development and/or commercialization.

The Company's lead program, motixafortide, is a cancer therapy platform currently being evaluated in a Phase 2a study for the treatment of pancreatic cancer in combination with KEYTRUDA and chemotherapy under a collaboration agreement with MSD. Motixafortideis also being evaluated in a Phase 2b study in consolidation AML and a Phase 3 study in stem cell mobilization for autologous bone-marrow transplantation.

BioLineRx is developing a second oncology program, AGI-134, an immunotherapy treatment for multiple solid tumors that is currently being investigated in a Phase 1/2a study.

For additional information on BioLineRx, please visit the Company's website at http://www.biolinerx.com, where you can review the Company's SEC filings, press releases, announcements and events. BioLineRx industry updates are also regularly updated on Facebook,Twitter, and LinkedIn.

Various statements in this release concerning BioLineRx's future expectations constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "may," "expects," "anticipates," "believes," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Some of these risks are: changes in relationships with collaborators; the impact of competitive products and technological changes; risks relating to the development of new products; and the ability to implement technological improvements. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 28, 2019. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

Contact:

Tim McCarthyLifeSci Advisors, LLC+1-212-915-2564tim@lifesciadvisors.com

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Tsipi HaitovskyPublic Relations+972-52-598-9892tsipihai5@gmail.com

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SOURCE BioLineRx Ltd.

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BioLineRx Announces Notice of Allowance from USPTO for Patent Covering Motixafortide (BL-8040) in Combination With Anti-PD-1 for the Treatment of Any...

Lance was diagnosed with cerebral palsy a year ago. His family hopes non-FDA approved stem cell treatment for the disease can help him walk and talk.

CAMP HILL, Pa. A family in Cumberland County has turned to stem cells to treat their two-year-old son diagnosed with cerebral palsy. The only problem: stem cell treatment for the disease hasn't been approved by the FDA.

The day he was born, when he wheeled him down the hall and he was only a pound, and I started to cry and said, will he live? And he said, of course Hes only small," said Danielle Maxwell, Lance's mom.

The words, "he's only small," are what Lance's mom and father Rob have lived by since the day he was born. The preemie, born three months early, has been through several surgeries and complications along the way. But, Lance has always been a fighter.

Lance fought so hard just to survive the beginning of life, and come home with us," said Danielle. "And he is just so happy and loving and amazing.

About a year ago, Lance was diagnosed with cerebral palsy. Doctors told his family, he will never walk, talk or take care of himself.

We just dont believe that," said Danielle. "We dont.

Lance receives a lot of different therapies but, his parents did not want to just stop there.

We both overwhelmingly feel, he never gave up, he never gave up on us, he never gave up on himself," said Rob. "So, we owe it to him to give him the opportunity. Its really that simple, he deserves the opportunity."

Danielle began researching stem cell therapies, even speaking to doctors in countries overseas where treatment with stem cells is more readily accessible than in the U.S. The FDA has approved stem cell treatments for some conditions but not cerebral palsy. However, trials to determine the effectiveness of stem cell treatment for the disease are underway.

What weve seen is a small but real appearing improvement in motor function," said Doctor Charles Cox with University of Texas Health in Houston, began a trial in 2013 on the safety and effectiveness of banked cord blood or bone marrow stem cells in children with cerebral palsy, and is now just wrapping up the results from the trial.

The overall results of this study depend if youre a glass half full or half empty kind of person," said Dr. Cox. "It is not a compelling miraculous result. Its not, Oh my God, this child was treated and look at this profound benefit.'"

Because stem cell treatment for cerebral palsy is still in trial phases, it's not approved treatment by the FDA. However, the Maxwells did find a doctor in Harrisburg willing to transfer stem cells from a full-term baby's umbilical cord to Lance. But, since it isn't FDA approved, we were not allowed to be there to show Lance receiving the stem cells. The Maxwells are hopeful following this procedure Lance may someday walk and more importantly be able to communicate with them.

He wants to be involved," said Rob. "You can tell hes trying to communicate he just cant get over that hump. We believe stem cells could be that bridge to help him move a little faster.

Danielle says, it will take about six months to see if the stem cells will have any definitive benefits for Lance. But, already says she's seeing progress. She says Lance is not able to stand on his own.

More:
Cumberland County family turns to non-FDA approved stem cell treatment to help two-year-old son with cerebral palsy - FOX43.com

Feb 25, 2020 12:00 AM

Every ten minutes, someone passes away from a blood disorder. Thats 148 people a day. There is a way to prevent many of these deathsa bone marrow transplant. DNA matching has the power to help thousands of people waiting for a life-saving bone marrow donation, but this special donor list depends entirely upon the willingness of individuals to sign up. Could your unique DNA hold the match that helps one person live to see tomorrow? Heres how you can find out.

Be The Match is a global hub for bone marrow donor registry working with hundreds of partners to support the transplant community. Signing up is easy online. You provide registration information, receive a kit in the mail, use the DNA swab as directed, and send it back for DNA typing. Your potentially life-saving information is secure and becomes available to specialized doctors around the world.

Even if you arent a match right away, the fact that every three minutes a person is diagnosed with a blood disorder means you could be called at any time to be a hero in someones time of need. Paloma Cariello, MD, MPH, says, Its absolutely a life-saving procedure. Its a new life that people getwe call it a new birthday, and at many hospitals they give it as a new birthday date in their chart. We sing Happy Birthday. Its a big event.

To find a close enough match to help fortify a patients immune system, doctors have to be precise. They first reach out to family, but even then, only 30% of patients find a good match. The odds of finding a match in an unrelated donor can be as low as 18%, especially with minorities.

The need for more individuals of every background cannot be overstated, says University of Utah Health Hematologist Sagar Patel, MD. He emphasizes the need for ethnic minorities to register. Every ethnicity is represented in the pool of patients, so the donor pool likewise needs to be diversified to improve the availability of similar DNA typing.

If a doctor finds you to be a suitable match, they select the ideal method for their patient and prepare you for donation. There are two donation methods: peripheral blood stem cell (PBSC) donation and bone marrow donation. Because every donor is carefully screened and prepared, and because a small amount of fluid is ultimately needed, neither procedure method impacts the performance of your own immune system, says Cariello.

With PBSC retrieval, you receive a stimulant for five days to increase the presence of blood-forming cells in your blood stream. Then a refined process of extraction occurs: Your blood is drawn, a machine collects just the cells the patient needs, and your remaining fluids are safely returned to you. This process can usually be done in one eight-hour session. Most donors report a full recovery within a week to 10 days, but you will be followed-up with until your full recovery.

If the doctor determines that the patient needs bone marrow, your procedure is a bit different. Marrow needs to be drawn from your pelvic bones. It happens in a hospital and under anesthesia, and you will feel no pain as the donation is collected. You can go back to routine activity the same day, and your system fully replenishes within four to six weeks.

Even with thousands of people in need, only about one in 430 donors in the Be The Match system are called in as a match. And the simple processes and expert professional care you receive minimize potential risk. A common side effect is bruising at the procedure sites, and some donors occasionally experience mild pain, fatigue, or dizziness. Reactions related to the use of anesthesia might also occur.

With such little risk, it shouldnt be a question as to whether you sign up, but when. And today is a perfect day. The low odds of finding a cure that these patients face are as extreme as the high rewards that await themand youwhen you make the choice to become a donor. Visit BeTheMatch.org to learn more and to become the one who initiates the miraculous call: We found a match.

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Be a Bone Marrow Hero - University of Utah Health Care