Meet HSCI #39;s Amar Sahay, PhD
Amar Sahay, PhD, is an Assistant Professor at the Center for Regenerative Medicine and the Department of Psychiatry at Massachusetts General Hospital, Harvar...

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BioLamina Symposium 2014 Biorelevant Approaches to Regenerative Medicine Cell-Based Assays Part I
Introduction to the 2014 BioLamina Symposium on Biorelevant Approaches to Regenerative Medicine Cell-Based Assays by Prof. Karl Tryggvason. He talks about ...

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BioLamina Symposium 2014 Biorelevant Approaches to Regenerative Medicine Cell-Based Assays Part II
Prof. Outi Hovatta explains human embryonic stem cells from the first derivation to clinical grade cells Human embryonic stem cells (hESC) were originally derived using mouse fetal fibroblasts...

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BioLamina Symposium 2014 Biorelevant Approaches to Regenerative Medicine Cell-Based Assay Part III
Sergey Rodin walks us through his new Nature communications article http://bit.ly/1nDFgf0 Laminin-521 and -511 are versatile substrata for long-term self-ren...

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BioLamina Symposium 2014 Biorelevant Approaches to Regenerative Medicine Cell-Based Assays Part IV
Sonya Stenfelt PhD at Karolinska Institute talks about Embryonic stem cell-based therapy for advanced macula degeneration Our objective is to develop a safe ...

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BioLamina Symposium 2014 Biorelevant Approaches to Regenerative Medicine Cell-Based Assays Part V
PhD Anna Domogatskaya talks about how biologically relevant laminins enable mouse pancreatic islets in vitro culture: expansion, phenotype maintenance and gl...

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BioLamina Symposium 2014 Biorelevant Approaches to Regenerative Medicine Cell-Based Assays Part VI
PhD Anna Falk from the Karolinska institute talks about The role of neural stem cells in neurodevelopmental disorders For psychiatric diseases, which later in life manifest in impairment of...

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Platelet rich plasma in regenerative medicine

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Stem cell treatment Multiple Sclerosis
Patient suffering from multiple sclerosis undergone stemcell treatment.

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Advancing Toward Multiple Sclerosis Therapies Using Stem Cells
For more info about the California stem cell agency #39;s MS research funding, visit our fact sheet: http://go.usa.gov/84sP Dr. Tom Lane of the University of Utah (formerly a CIRM grantee at UC...

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Advancing Toward Multiple Sclerosis Therapies Using Stem Cells - Video

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Infusio By Philip Battiade
Philip Battiade discusses the many benefits to stem cell therapy for chronic illnesses.

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Mice have been poked, prodded, injected and dissected in the name of science. But there are limits to what mice can teach us especially when it comes to stem cell therapies. For the first time, researchers haveturned skin cells into bone in a creature more closely related to humans: monkeys.

In a study published Thursday in the journal Cell Reports, scientists report that they regrew bone in 25rhesus macaques using induced pluripotent stem cells (iPSCs) taken from the creatures skin. Since macaques are more closely related to humans, their discovery could help push stem cell therapies into early clinical trials in humans.

While this is the good news, the bad news is that iPSCs can also seed tumors in monkeys; however, the tumors grew at a far slower rate than in previous studies in mice. This finding further emphasizes the key role primates likely will play in testing the safety of potential stem cell therapies.

Repairing Bone

Researchers used a common procedure to reprogram macaque skin cells, and coaxed them into pluripotent cells that were capable of building bone. They seeded these cells into ceramic scaffolds, which are already used by surgeons used to reconstruct bone. The cells took, and the monkeys successfully grew new bone.

In some experiments, the monkeys formed teratomas nasty tumors that can contain teeth and hair when they were injected with undifferentiated iPSCs, or cells that have the potential to change into any kind of cell. However, the tumors grew 20 times slower than in mice, highlighting an important difference between mice and monkeys.

Fortunately, tumors did not form in monkeys that were injected with differentiated iPSCs, or cells that were programmed to createbone cells.

Advancing Research

Researchers say their successful procedure proves that monkeys willplay an important rolein research on therapies using iPSCs. These monkeys will help scientists test and analyze risks associated with the therapies and improve their safety.

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PUBLIC RELEASE DATE:

15-May-2014

Contact: Mary Beth O'Leary moleary@cell.com 617-397-2802 Cell Press

Researchers have shown for the first time in an animal that is more closely related to humans that it is possible to make new bone from stem-cell-like induced pluripotent stem cells (iPSCs) made from an individual animal's own skin cells. The study in monkeys reported in the Cell Press journal Cell Reports on May 15th also shows that there is some risk that those iPSCs could seed tumors, but that unfortunate outcome appears to be less likely than studies in immune-compromised mice would suggest.

"We have been able to design an animal model for testing of pluripotent stem cell therapies using the rhesus macaque, a small monkey that is readily available and has been validated as being closely related physiologically to humans," said Cynthia Dunbar of the National Heart, Lung, and Blood Institute. "We have used this model to demonstrate that tumor formation of a type called a 'teratoma' from undifferentiated autologous iPSCs does occur; however, tumor formation is very slow and requires large numbers of iPSCs given under very hospitable conditions. We have also shown that new bone can be produced from autologous iPSCs, as a model for their possible clinical application."

Autologous refers to the fact that the iPSCs capable of producing any tissue typein this case bonewere derived from the very individual that later received them. That means that use of these cells in tissue repair would not require long-term or possibly toxic immune suppression drugs to prevent rejection.

The researchers first used a standard recipe to reprogram skin cells taken from rhesus macaques. They then coaxed those cells to form first pluripotent stem cells and then cells that have the potential to act more specifically as bone progenitors. Those progenitor cells were then seeded onto ceramic scaffolds that are already in use by reconstructive surgeons attempting to fill in or rebuild bone. And, it worked; the monkeys grew new bone.

Importantly, the researchers report that no teratoma structures developed in monkeys that had received the bone "stem cells." In other experiments, undifferentiated iPSCs did form teratomas in a dose-dependent manner.

The researchers say that therapies based on this approach could be particularly beneficial for people with large congenital bone defects or other traumatic injuries. Although bone replacement is an unlikely "first in human" use for stem cell therapies given that the condition it treats is not life threatening, the findings in a primate are an essential step on the path toward regenerative clinical medicine.

"A large animal preclinical model for the development of pluripotent or other high-risk/high-reward generative cell therapies is absolutely required to address issues of tissue integration or homing, risk of tumor formation, and immunogenicity," Dunbar said. "The testing of human-derived cells in vitro or in profoundly immunodeficient mice simply cannot model these crucial preclinical safety and efficiency issues."

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In this image, the top row shows the stem cells transplanted into the mouse spinal cord. The lower row shows a close-up of the stem cells (brown). By day 7 post-transplant, the stem cells are no longer detectable. Within this short period of time, the stem cells have sent chemical signals to the mouses own cells, enabling them to repair the nerve damage caused by MS. (image: Lu Chen)

For patients with multiple sclerosis (MS), current treatment options only address early-stage symptoms of the debilitating disease. Now, new research has found a potential treatment that could both stop disease progression and repair existing damage.

In a study published in Stem Cell Reports, researchers utilized a group of paralyzed mice genetically engineered to have an MS-like condition. Initially, the researchers set out to study the mechanisms of stem cell rejection in the mice. However, two weeks after injecting the mice with human neural stem cells, the researchers made the unexpected discovery that the mice had regained their ability to walk.

This had a lot of luck to do with it; right place, right time co-senior author Jeanne Loring, director of the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, California, told FoxNews.com. [co-senior author Tom Lane] called me up and said, Youre not going to believe this. He sent me a video, and it showed the mice running around the cages. I said, Are you sure these are the same mice?

Loring, whose lab specializes in turning human stem cells into neural precursor cells, or pluripotent cells, collaborated with Tom Lane, a professor of pathology at the University of Utah whose focus is on neuroinflammatory diseases of the central nervous system. The team was interested in stem cell rejection in MS models in order to understand the underlying molecular and cellular mechanisms contributing to rejection of potential stem cell therapies for the disease.

Multiple sclerosis is an autoimmune disease that affects more than 2.3 million people worldwide. For people with MS, the immune system misguidedly attacks the bodys myelin, the insulating coating on nerve fibers.

In a nutshell, its the rubber sheath that protects the electrical wire; the axon that extends from the nerves cell body is insulated by myelin, Lane, who began the study while at the University of California, Irvine, told FoxNews.com

Once the myelin has been lost, nerve fibers are unable to transmit electric signals efficiently, leading to symptoms such as vision and motor skill problems, fatigue, slurred speech, memory difficulties and depression.

The researchers inadvertent treatment appeared to work in two ways. First, there was a decrease of inflammation within the central nervous system of the mice, preventing the disease from progressing. Secondly, the injected cells released proteins that signaled cells to regenerate myelin and repair existing damage.

While the stem cells were rejected in the mice after 10 days, researchers were able to see improvements for up to six months after initial implantation.

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Mice severely disabled by a multiple sclerosis (MS) -- like condition could walk less than two weeks following treatment with human stem cells. The finding, which uncovers new avenues for treating MS, will be published online on May 15, 2014, in the journal Stem Cell Reports.

When scientists transplanted human stem cells into MS mice, they predicted the cells would be rejected, much like rejection of an organ transplant.

Expecting no benefit to the mice, they were surprised when the experiment yielded spectacular results.

"My postdoctoral fellow Dr. Lu Chen came to me and said, 'The mice are walking.' I didn't believe her," said co-senior author, Tom Lane, Ph.D., a professor of pathology at the University of Utah, who began the work at University of California, Irvine.

Within just 10 to 14 days, the mice regained motor skills. Six months later, they still showed no signs of slowing down.

"This result opens up a whole new area of research for us," said co-senior author Jeanne Loring, Ph.D., co-senior author and professor at The Scripps Research Institute in La Jolla, Calif.

More than 2.3 million people worldwide have MS, a disease where the immune system attacks myelin, an insulation layer surrounding nerve fibers. The resulting damage inhibits nerve impulses, producing symptoms that include difficulty walking, impaired vision, fatigue and pain.

The MS mice treated with human stem cells experience a reversal of symptoms. Immune attacks are blunted, and damaged myelin is repaired, explaining their dramatic recovery. The discovery could help patients with latter, or progressive, stages of the disease, for whom there are no treatments.

Counterintuitively, the researchers' original prediction that the mice would reject the stem cells, came true. There are no signs of the cells after one week. In that short window, they send chemical signals that instruct the mouse's own cells to repair the damage caused by MS. This realization could be important for therapy development.

"Rather than having to engraft stem cells into a patient, which can be challenging, we might be able to put those chemical signals into a drug that can be used to deliver the therapy much more easily," said Lane.

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Posted: Thursday, May 15, 2014, 12:00 PM

THURSDAY, May 15, 2014 (HealthDay News) -- Mice disabled by a multiple sclerosis-like condition were able to walk again a few weeks after receiving human neural stem cell transplants, a new study shows.

While research in mice often fails to pan out in humans, the researchers believe the finding hints at new ways to treat people with MS.

The mice with the MS-like condition had to be fed by hand because they could not stand long enough to eat and drink on their own. But within 10 to 14 days of receiving the human neural stem cells, the rodents regained the ability to walk, along with other motor skills. This improvement was still evident six months later, the researchers said.

The study authors said they were surprised by the results of what they believed was to be a routine experiment. They had expected that the transplanted cells would be rejected by the mice.

"My postdoctoral fellow Dr. Lu Chen came to me and said, 'The mice are walking.' I didn't believe her," study co-senior author Tom Lane, a professor of pathology at the University of Utah, said in a university news release.

The study was published online May 15 in the journal Stem Cell Reports.

"This result opens up a whole new area of research for us to figure out why it worked," co-senior author Jeanne Loring, director of the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, Calif., said in the news release.

The next step on the road toward possible clinical trials in people is to assess the safety and durability of the stem cell therapy in mice.

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Newswise LA JOLLA, CAMay 15, 2014Mice crippled by an autoimmune disease similar to multiple sclerosis (MS) regained the ability to walk and run after a team of researchers led by scientists at The Scripps Research Institute (TSRI), University of Utah and University of California (UC), Irvine implanted human stem cells into their injured spinal cords.

Remarkably, the mice recovered even after their bodies rejected the human stem cells. When we implanted the human cells into mice that were paralyzed, they got up and started walking a couple of weeks later, and they completely recovered over the next several months, said study co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.

Thomas Lane, an immunologist at the University of Utah who co-led the study with Loring, said he had never seen anything like it. Weve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring's lab provided, said Lane, who began the study at UC Irvine.

The mices dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans.

"This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients, said co-author Craig Walsh, a UC Irvine immunologist.

Stem Cell Therapy for MS

MS is an autoimmune disease of the brain and spinal cord that affects more than a half-million people in North America and Europe, and more than two million worldwide. In MS, immune cells known as T cells invade the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating on nerve fibers called myelin. Affected nerve fibers lose their ability to transmit electrical signals efficiently, and this can eventually lead to symptoms such as limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression.

Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers. But they are only partially effective and often have significant adverse side effects. Lorings group at TSRI has been searching for another way to treat MS using human pluripotent stem cells, which are cells that have the potential to transform into any of the cell types in the body.

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Newswise (SALT LAKE CITY) - Mice severely disabled by a multiple sclerosis (MS) like condition could walk less than two weeks following treatment with human stem cells. The finding, which uncovers new avenues for treating MS, will be published online on May 15, 2014, in the journal Stem Cell Reports.

When scientists transplanted human stem cells into MS mice, they predicted the cells would be rejected, much like rejection of an organ transplant.

Expecting no benefit to the mice, they were surprised when the experiment yielded spectacular results.

My postdoctoral fellow Dr. Lu Chen came to me and said, The mice are walking. I didnt believe her, said co-senior author, Tom Lane, Ph.D., a professor of pathology at the University of Utah, who began the work at University of California, Irvine.

Within just 10 to 14 days, the mice regained motor skills. Six months later, they still showed no signs of slowing down.

This result opens up a whole new area of research for us, said co-senior author Jeanne Loring, Ph.D., co-senior author and professor at The Scripps Research Institute in La Jolla, Calif.

More than 2.3 million people worldwide have MS, a disease where the immune system attacks myelin, an insulation layer surrounding nerve fibers. The resulting damage inhibits nerve impulses, producing symptoms that include difficulty walking, impaired vision, fatigue and pain.

The MS mice treated with human stem cells experience a reversal of symptoms. Immune attacks are blunted, and damaged myelin is repaired, explaining their dramatic recovery. The discovery could help patients with latter, or progressive, stages of the disease, for whom there are no treatments.

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Dr. Broyles #39; Cartilage Regeneration: Why Bone Marrow Stem Cells?
Dr. Broyles highlights the differences between Dr. Saw #39;s methods and his own, including FDA regulations in the US regarding autologous stem cells. For more i...

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THURSDAY, May 15, 2014 (HealthDay News) -- Although the very concept of cancer stem cells has been controversial, new research provides proof that these distinct types of cells exist in humans.

Using genetic tracking, researchers found that a gene mutation tied to cancer's development can be traced back to cancer stem cells. These cells are at the root of cancer and responsible for supporting the growth and progression of the disease, the scientists report.

Cancer stem cells are able to replenish themselves and produce other types of cancer cells, just as healthy cells produce other normal cells, the study's British and European authors explained.

"It's like having dandelions in your lawn. You can pull out as many as you want, but if you don't get the roots they'll come back," study first author Dr. Petter Woll, of the MRC Weatherall Institute for Molecular Medicine at the University of Oxford, said in a university news release.

The researchers, led by a team of scientists at Oxford and the Karolinska Institute in Sweden, said their findings could have significant implications for cancer treatment. They explained that by targeting cancer stem cells, doctors could not only get rid of a patient's cancer but also prevent any remaining cancer cells from sustaining the disease.

The study, published May 15 in Cancer Cell, involved 15 patients diagnosed with myelodysplastic syndromes (MDS), a type of cancer that often develops into acute myeloid leukemia, a form of blood cancer.

The researchers examined the cancer cells in the patients' bone marrow. Four of the patients were also monitored over time. One patient was followed for two years. Two patients were followed for 30 months and another patient was monitored for 10 years.

According to the researchers, in prior studies citing the existence of cancer stem cells, the lab tests that were used to identify these cells were considered by many to be unreliable.

However, "In our studies we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients," explained study leader Sten Eirik Jacobsen, of Oxford's MRC Molecular Haematology Unit and the Weatherall Institute for Molecular Medicine.

According to the research, a distinct group of MDS cells had all the characteristics of cancer stem cells, and only these particular cancer cells appeared able to cause tumor spread.

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May 15, 2014 This shows C57BL/6 mice, the common strain of laboratory mouse, in a Cambridge animal house. This breed of animal was used in the 'heavy mouse' study. Credit: University of Cambridge

Scientists have created a 'heavy' mouse, the world's first animal enriched with heavy but non-radioactive isotopes - enabling them to capture in unprecedented detail the molecular structure of natural tissue by reading the magnetism inherent in the isotopes.

This data has been used to grow biological tissue in the lab practically identical to native tissue, which can be manipulated and analysed in ways impossible for natural samples. Researchers say the approach has huge potential for scientific and medical breakthroughs: lab-grown tissue could be used to replace heart valves, for example.

In fact, with their earliest research on the new in vitro tissue, the team have discovered that poly(ADP ribose) (PAR) a molecule believed to only exist inside a cell for the purpose of repairing DNA not only travels outside cells but may trigger bone mineralisation.

"It was crazy to see PAR behaving in this way; it took six months of detailed analysis and many more experiments to convince ourselves," said Dr Melinda Duer from Cambridge's Department of Chemistry, who led the study, published today in the journal Science.

"I think this is just the first of many discoveries that will stem from the heavy mouse. Isotope-enriched proteins and cells are fairly commonplace now, but the leap to a whole animal is a big one.

"The heavier nuclei in the carbon isotopes changes the rate of chemical reactions, and many people myself initially included didn't believe you could enrich a whole animal with them. But it worked beautifully," she said.

The research, funded by the Biotechnology and Biological Sciences Research Council and British Heart Foundation, could lead to improved success rates for medical implants and reduce the need for animals in research, as well as opening up an entirely new approach for biochemical investigation.

The team used a technique called Nuclear Magnetic Resonance spectroscopy (NMR) that can read the magnetic nuclei found in certain isotopes, such as carbon-13 which has one neutron more than most carbon.

But carbon-13 makes up only 1% of the carbon in our bodies, nowhere near enough to do useful NMR. However, the researchers managed to get the carbon of a mouse up to 20% carbon-13.

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Concerns that stem cells could cause cancer in recipients are fading further with a new study

New bone formation (stained bright green under ultra-violet light) was seen in monkeys given their own reprogrammed stem cells. Courtesy of Nature magazine

A major concern over using stem cells is the risk of tumors: but now a new study shows that It takes a lot of effort to get induced pluripotent stem (iPS) cells to grow into tumors after they have been transplanted into a monkey. The findings will bolster the prospects of one day using such cells clinically in humans.

Making iPS cells from an animal's own skin cells and then transplanting them back into the creature also does not trigger an inflammatory response as long as the cells have first been coaxed to differentiate towards a more specialized cell type. Both observations, published inCell Reports today, bode well for potential cell therapies.

It's important because the field is very controversial right now, saysAshleigh Boyd,a stem-cell researcher at University College London, who was not involved in the work. It is showing that the weight of evidence is pointing towards the fact that the cells won't be rejected.

Pluripotent stem cells can be differentiated into many different specialized cell types in culture and so are touted for their potential as therapies to replace tissue lost in diseases such as Parkinsons and some forms of diabetes and blindness. iPS cells, which are made by reprogramming adult cells, have an extra advantage because transplants made from them could be genetically matched to the recipient.

Researchers all over the world are pursuing therapies based on iPS cells, and a group in Japan began enrolling patients for a human study last year. But work in mice has suggested controversially that even genetically matched iPS cellscan trigger an immune response, and pluripotent stem cells can also form slow-growing tumors, another safety concern.

Closer to human Cynthia Dunbar, a stem-cell biologist at the National Institutes of Health in Bethesda, Maryland, who led the new study, decided to evaluate both concerns in healthy rhesus macaques. Human stem cells are normally only studied for their ability to form tumors in mice as a test of pluripotency if the animals immune systems are compromised, she says.

We really wanted to set up a model that was closer to human. It was somewhat reassuring that in a normal monkey with a normal immune system you had to give a whole lot of immature cells to get any kind of tumour to grow, and they were very slow growing.

Dunbar and her team made iPS cells from skin and white blood cells from two rhesus macaques, and transplanted the iPS cells back into the monkeys that provided them. It took 20 times as many iPS cells to form a tumor in a monkey, compared with the numbers needed in an immunocompromised mouse. Such information will be valuable for assessing safety risks of potential therapies, Dunbar says. And although the iPS cells did trigger a mild immune response attracting white blood cells and causing local inflammation iPS cells that had first been differentiated to a more mature state did not.

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A number of ingredients like ceramides, collagen, stem cells and antioxidants that are commonly associated with cosmetics are being featured in products for the hair. Do they work as well?

In the quest for a healthy and shining mane, a number of new products are being launched in the market on a regular basis. It has been observed that many of these are said to contain elements that are normally associated with skin care. Products with collagen, ceramides, hyaluronic acid, stem cells and so on have long been proven beneficial to plump up skin, reduce fine lines, lighten dark spots and keep skin healthy and radiant. However, recently a number of these have been seen in hair care products like shampoos and conditioners. The question remains though is of they work just as well on the mane. Copper peptides, for example is considered an effective skin regeneration ingredient and research shows it works well for the scalp too producing thicker, healthier hair. Ceramides can be effective in forming a protective coat around the hair shaft and strengthening it, while collagen helps hair hold onto moisture making it look thicker and fuller. Antioxidants are said to neutralise the free radicals preventing dullness of locks.

SCALP IS SIMILAR TO SKIN Tisha Kapur Khurana, beauty expert and executive director, Bottega di Lungavita explains similar ingredients can be used on the skin and hair sometimes because the scalp is covered with thicker skin similar to the rest of our body. It is a thick layer of skin with many sebaceous glands which produce oil or sebum to protect the hair. Collagen is a protein that is found in the body and is a necessity for good health. The collagen supplements let hair grow long and strong. It increases the body's natural hair-building proteins. Moreover, if applied to the scalp, it can reduce the look and dryness of grey hair. Even stem cells work as the hair follicles contain cells which may lead to successfully treating baldness. When buying a product you should always consider the hair type curly or straight as well as thick or fine and accordingly choose products, she says.

BE CAREFUL It is advisable not to use similar products for your hair and skin. Your skin is very tender and it needs really mild products to cleanse and clear the dirt and impurities. On the other hand, while you do need mild products for your hair as well, the shampoos and conditioners are mild but effective enough to cleanse the grime, dandruff and other impurities that get lodged in your scalp, explains Priti Mehta, founder and director, Omved. She adds, Standard cosmetics often include synthetic and sometimes even animal-derived ingredients. When you use natural options for your skin and hair, it is likely to help your skin feel and breathe better. Anything that has SLS, parabens, preservatives, fragrance, and colours to name a few listed on it should be avoided.

HAVE SOME BENEFITS Dr Apratim Goel, dermatologist, Cutis Skin Studio says some of these ingredients can work. Collagen or ceramides are larger molecules which are doubtful on skin as well. However these ingredients have been used regularly in hair care products. However, there is no controlled studies of efficacy of these ingredients in hair. Stem cells and antioxidants, though, do work for hair. Stem cell injections are a regular treatment for boosting hair growth. Further, plant stem cells are available as hair serums and give good results against hair loss. Regarding antioxidants, they are very important for hair care as hair especially coloured or treated locks are very prone to damage from sun as well as chemical exposure.

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Newswise CAMBRIDGE, Mass. (May 15, 2014) By studying nerve and liver cells grown from patient-derived induced pluripotent stem cells (iPSCs), Whitehead Institute researchers have identified a potential dual-pronged approach to treating Niemann-Pick type C (NPC) disease, a rare but devastating genetic disorder.

According to the National Institutes of Health (NIH), approximately 1 in 150,000 children born are afflicted with NPC, the most common variant of Niemann-Pick. Children with NPC experience abnormal accumulation of cholesterol in their liver and nerve cells, leading to liver failure, neurodegeneration, andultimatelydeath, often before age 10.

Although there is currently no effective treatment for NPC disease, a clinical trial examining potential cholesterol-lowering effects of the drug cyclodextrin in NPC patients is ongoing. However, research in Whitehead Founding Member Rudolf Jaenischs lab led by Dorothea Matezel along with Sovan Sarkar suggests that the high doses may actually be harmful. This and other findings are reported this week in the journal Stem Cell Reports.

At those levels of cyclodextrin (in the clinical trial), Maetzel and her coauthors show that cells encounter a further block in autophagy that could be detrimental, says Jaenisch, who is also a professor of biology at Massachusetts Institute of Technology. But when they use it at a lower dose in combination with another small molecule, carbamazepine, which stimulates autophagy, then it significantly improves the survival of the cells. Such an approach lowers cholesterol levels and restores the autophagy defects at the same time. This could be a new type of treatment for NPC disease.

To clarify what is amiss in NPC and identify potential therapeutics that could correct these problems, Maetzel generated iPSCs from patients with the most common genetic mutation that causes NPC. She created the iPSCs by pushing skin cells donated by the patients back to an embryonic stem cell-like state. These iPSCs were differentiated into liver and neuronal cells, the cell types most affected in NPC. Along with Haoyi Wang, a postdoctoral researcher in the Jaenisch lab, she then corrected one copy of the causal mutation, in the NPC1 gene, to create control cells whose genomes differ only at the single edited gene copy.

When Maetzel and Sarkar analyzed the cellular functions in the NPC1-mutant and control cell lines, they determined that although cholesterol does build up in the NPC1-mutant cells, a more significant problem is defective autophagya basic cellular function that degrades and recycles unneeded or faulty molecules, components, or organelles in a cell. The impaired autophagy prevents normal elimination of its cargo, such as damaged organelles or other substrates like p62, which then accumulates and damages the cells. The finding confirms previous work from the Jaenisch lab linking the NPC1 mutation to defective autophagy in mouse cells.

Autophagy dysfunction has major implications in several neurodegenerative and certain liver conditions, and therefore autophagy modulators have tremendous biomedical relevance, says Sarkar. We wanted to screen for compounds stimulating autophagy in human disease-relevant cells and show the beneficial effects of such an approach in the context of a lipid/lysosomal storage disorder.

Maetzel and Sarkar used the two types of human disease-affected cells to screen for compounds known to improve autophagy but not impacting on the mammalian target of rapamycin (mTOR) pathway, which has critical cellular functions and also controls autophagy. They found only one capable of jumpstarting autophagy independently of mTOR in both liver and nerve cells. When this drug, carbamazepine, which is a mood stabilizer prescribed for bipolar disorder, was added in combination with low doses of cyclodextrin, both cholesterol accumulation and autophagy defects were rescued in the NPC-mutated cells.

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