Rewind 2022: Innovative research, slew of crucial FDA approvals and new strides in genetic therapies became pivotal moments  The Financial Express

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Rewind 2022: Innovative research, slew of crucial FDA approvals and new strides in genetic therapies became pivotal moments - The Financial Express

Recommendation and review posted by Bethany Smith

Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek , meaning of the body), they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

Scientific interest in adult stem cells is centered around two main characteristics. The first of which, being their ability to divide or self-renew indefinitely, and secondly, their ability to generate all the cell types of the organ from which they originate, potentially regenerating the entire organ from a few cells.[1] Unlike embryonic stem cells, the use of human adult stem cells in research and therapy is not considered to be controversial, as they are derived from adult tissue samples rather than human embryos designated for scientific research. The main functions of adult stem cells are to replace cells that are at risk of possibly dying as a result of disease or injury and to maintain a state of homeostasis within the cell.[2] There are three main methods to determine if the adult stem cell is capable of becoming a specialized cell.[2] The adult stem cell can be labeled in vivo and tracked, it can be isolated and then transplanted back into the organism, and it can be isolated in vivo and manipulated with growth hormones.[2] They have mainly been studied in humans and model organisms such as mice and rats.

A stem cell possesses two properties:

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter stem cells, whereas asymmetric division produces one stem cell and one progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) and their associated proteins between the daughter cells.[5]

Under normal conditions, tissue stem cells divide slowly and infrequently. They exhibit signs of quiescence, or reversible growth arrest.[6] The niche the stem cell is found in plays a large role in maintaining quiescence.[6] Perturbed niches cause the stem cell to begin actively dividing again to replace lost or damaged cells until the niche is restored. In hematopoietic stem cells, the MAPK/ERK pathway and PI3K/AKT/mTOR pathway regulate this transition.[7] The ability to regulate the cell cycle in response to external cues helps prevent stem cell exhaustion, or the gradual loss of stem cells following an altered balance between dormant and active states. Infrequent cell divisions also help reduce the risk of acquiring DNA mutations that would be passed on to daughter cells.

Discoveries in recent years have suggested that adult stem cells might have the ability to differentiate into cell types from different germ layers. For instance, neural stem cells from the brain, which are derived from ectoderm, can differentiate into ectoderm, mesoderm, and endoderm.[8] Stem cells from the bone marrow, which is derived from mesoderm, can differentiate into liver, lung, GI tract and skin, which are derived from endoderm and mesoderm.[9] This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be induced by modifying the growth medium when stem cells are cultured in vitro or transplanting them to an organ of the body different from the one they were originally isolated from. There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity. More recent findings suggest that pluripotent stem cells may reside in blood and adult tissues in a dormant state.[10] These cells are referred to as "Blastomere Like Stem Cells" (BLSCs)[11] and "very small embryonic like" (VSEL) stem cells, and display pluripotency in vitro.[10] As BLSCs and VSEL cells are present in virtually all adult tissues, including lung, brain, kidneys, muscles, and pancreas,[12] co-purification of BLSCs and VSEL cells with other populations of adult stem cells may explain the apparent pluripotency of adult stem cell populations. However, recent studies have shown that both human and murine VSEL cells lack stem cell characteristics and are not pluripotent.[13][14][15][16]

Stem cell function becomes impaired with age, and this contributes to progressive deterioration of tissue maintenance and repair.[17] A likely important cause of increasing stem cell dysfunction is age-dependent accumulation of DNA damage in both stem cells and the cells that comprise the stem cell environment.[17] (See also DNA damage theory of aging.)

Adult stem cells can, however, be artificially reverted to a state where they behave like embryonic stem cells (including the associated DNA repair mechanisms). This was done with mice as early as 2006[citation needed] with future prospects to slow down human aging substantially. Such cells are one of the various classes of induced stem cells.

Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.

Hematopoietic stem cells (HSCs) are stem cells that can differentiate into all blood cells.[21] This process is called haematopoiesis.[22] Hematopoietic stem cells are found in the bone marrow and umbilical cord blood.[23] The HSC are generally dormant when found in adults due to their nature.[24]

Mammary stem cells provide the source of cells for growth of the mammary gland during puberty and gestation and play an important role in carcinogenesis of the breast.[25] Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland and have been shown to have the ability to regenerate the entire organ in mice.[25]

Intestinal stem cells divide continuously throughout life and use a complex genetic program to produce the cells lining the surface of the small and large intestines.[26] Intestinal stem cells reside near the base of the stem cell niche, called the crypts of Lieberkuhn. Intestinal stem cells are probably the source of most cancers of the small intestine and colon.[27]

Mesenchymal stem cells (MSCs) are of stromal origin and may differentiate into a variety of tissues. MSCs have been isolated from placenta, adipose tissue, lung, bone marrow and blood, Wharton's jelly from the umbilical cord,[28] and teeth (perivascular niche of dental pulp and periodontal ligament).[29] MSCs are attractive for clinical therapy due to their ability to differentiate, provide trophic support, and modulate innate immune response.[28] These cells have the ability to differentiate into various cell types such as osteoblasts, chondroblasts, adipocytes, neuroectodermal cells, and hepatocytes.[30] Bioactive mediators that favor local cell growth are also secreted by MSCs. Anti-inflammatory effects on the local microenvironment, which promote tissue healing, are also observed. The inflammatory response can be modulated by adipose-derived regenerative cells (ADRC) including mesenchymal stem cells and regulatory T-lymphocytes. The mesenchymal stem cells thus alter the outcome of the immune response by changing the cytokine secretion of dendritic and T-cell subsets. This results in a shift from a pro-inflammatory environment to an anti-inflammatory or tolerant cell environment.[31][32]

Endothelial stem cells are one of the three types of multipotent stem cells found in the bone marrow. They are a rare and controversial group with the ability to differentiate into endothelial cells, the cells that line blood vessels as well as lymphatic vessels. Endothelial stem cells are an important aspect in the vascular network, even influencing the motion relating to white blood cells.

The existence of stem cells in the adult brain has been postulated following the discovery that the process of neurogenesis, the birth of new neurons, continues into adulthood in rats.[33] The presence of stem cells in the mature primate brain was first reported in 1967.[34] It has since been shown that new neurons are generated in adult mice, songbirds and primates, including humans. Normally, adult neurogenesis is restricted to two areas of the brain the subventricular zone, which lines the lateral ventricles, and the dentate gyrus of the hippocampal formation.[35] Although the generation of new neurons in the hippocampus is well established, the presence of true self-renewing stem cells there has been debated.[36] Under certain circumstances, such as following tissue damage in ischemia, neurogenesis can be induced in other brain regions, including the neocortex.

Neural stem cells are commonly cultured in vitro as so called neurospheres floating heterogeneous aggregates of cells, containing a large proportion of stem cells.[37] They can be propagated for extended periods of time and differentiated into both neuronal and glia cells, and therefore behave as stem cells. However, some recent studies suggest that this behaviour is induced by the culture conditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication cycles in vivo.[38] Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.[39]

Neural stem cells share many properties with haematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system.[40]

Olfactory adult stem cells have been successfully harvested from the human olfactory mucosa cells, which are found in the lining of the nose and are involved in the sense of smell.[41] If they are given the right chemical environment, these cells have the same ability as embryonic stem cells to develop into many different cell types. Olfactory stem cells hold the potential for therapeutic applications and, in contrast to neural stem cells, can be harvested with ease without harm to the patient. This means they can be easily obtained from all individuals, including older patients who might be most in need of stem cell therapies.

Hair follicles contain two types of stem cells, one of which appears to represent a remnant of the stem cells of the embryonic neural crest. Similar cells have been found in the gastrointestinal tract, sciatic nerve, cardiac outflow tract and spinal and sympathetic ganglia. These cells can generate neurons, Schwann cells, myofibroblast, chondrocytes and melanocytes.[42][43]

Multipotent stem cells with a claimed equivalency to embryonic stem cells have been derived from spermatogonial progenitor cells found in the testicles of laboratory mice by scientists in Germany[44][45][46] and the United States,[47][48][49][50] and, a year later, researchers from Germany and the United Kingdom confirmed the same capability using cells from the testicles of humans.[51] The extracted stem cells are known as human adult germline stem cells (GSCs)[52]

Multipotent stem cells have also been derived from germ cells found in human testicles.[53]

Adult stem cell treatments have been used for many years to successfully treat leukemia and related bone/blood cancers utilizing bone marrow transplants.[54] The use of adult stem cells in research and therapy is not considered as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo.

Early regenerative applications of adult stem cells has focused on intravenous delivery of blood progenitors known as Hematopetic Stem Cells (HSC's). CD34+ hematopoietic Stem Cells have been clinically applied to treat various diseases including spinal cord injury,[55] liver cirrhosis[56] and Peripheral Vascular disease.[57] Research has shown that CD34+ hematopoietic Stem Cells are relatively more numerous in men than in women of reproductive age group among spinal cord Injury victims.[58] Other early commercial applications have focused on Mesenchymal Stem Cells (MSCs). For both cell lines, direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.[59] Clinical case reports in orthopedic applications have been published. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60] Centeno et al. have reported high field MRI evidence of increased cartilage and meniscus volume in individual human clinical subjects as well as a large n=227 safety study.[61][62][63] Many other stem cell based treatments are operating outside the US, with much controversy being reported regarding these treatments as some feel more regulation is needed as clinics tend to exaggerate claims of success and minimize or omit risks.[64]

The therapeutic potential of adult stem cells is the focus of much scientific research, due to their ability to be harvested from the parent body that is females during the delivery.[65][66][67] In common with embryonic stem cells, adult stem cells have the ability to differentiate into more than one cell type, but unlike the former they are often restricted to certain types or "lineages". The ability of a differentiated stem cell of one lineage to produce cells of a different lineage is called transdifferentiation. Some types of adult stem cells are more capable of transdifferentiation than others, but for many there is no evidence that such a transformation is possible. Consequently, adult stem therapies require a stem cell source of the specific lineage needed, and harvesting and/or culturing them up to the numbers required is a challenge.[68][69] Additionally, cues from the immediate environment (including how stiff or porous the surrounding structure/extracellular matrix is) can alter or enhance the fate and differentiation of the stem cells.[70]

Pluripotent stem cells, i.e. cells that can give rise to any fetal or adult cell type, can be found in a number of tissues, including umbilical cord blood.[71] Using genetic reprogramming, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[72][73][74][75] Other adult stem cells are multipotent, meaning there are several limited types of cell they can become, and are generally referred to by their tissue origin (such as mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).[76][77] A great deal of adult stem cell research has focused on investigating their capacity to divide or self-renew indefinitely, and their potential for differentiation.[78] In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.[79]

In recent years, acceptance of the concept of adult stem cells has increased. There is now a hypothesis that stem cells reside in many adult tissues and that these unique reservoirs of cells not only are responsible for the normal reparative and regenerative processes but are also considered to be a prime target for genetic and epigenetic changes, culminating in many abnormal conditions including cancer.[80][81] (See cancer stem cell for more details.)

Adult stem cells express transporters of the ATP-binding cassette family that actively pump a diversity of organic molecules out of the cell.[82] Many pharmaceuticals are exported by these transporters conferring multidrug resistance onto the cell. This complicates the design of drugs, for instance neural stem cell targeted therapies for the treatment of clinical depression.

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Adult stem cell - Wikipedia

Recommendation and review posted by Bethany Smith

Stem cells have been the object of much excitement and controversy amongst both scientists and the general population. Surprisingly, though, not everybody understands the basic properties of stem cells, let alone the fact that there is more than one type of cell that falls within the stem cell category. Here, Ill lay out the basic concepts of stem cell biology as a background for understanding the stem cell research field, where it is headed, and the enormous promise it offers for regenerative medicine.

Fertilization of an egg cell by a sperm cell results in the generation of a zygote, the single cell that, upon a myriad of divisions, gives rise to our whole body. Because of this amazing developmental potential, the zygote is said to be totipotent. Along the way, the zygote develops into the blastocyst, which implants into the mothers uterus. The blastocyst is a structure comprising about 300 cells that contains two main regions: the inner cell mass (ICM) and the trophoblast. The ICM is made of embryonic stem cells (ES cells), which are referred to as pluripotent. They are able to give rise to all the cells in an embryo proper, but not to extra-embryonic tissues, such as the placenta. The latter originate from the trophoblast [].

Even though it is hard to pinpoint exactly when or by whom what we now call stem cells were first discovered, the consensus is that the first scientists to rigorously define the key properties of a stem cell were Ernest McCulloch and James Till. In their pioneering work in mice in the 1960s, they discovered the blood-forming stem cell, the hematopoietic stem cell (HSC) [2, 3]. By definition, a stem cell must be capable of both self-renewal (undergoing cell division to make more stem cells) and differentiation into mature cell types. HSCs are said to be multipotent, as they can still give rise to multiple cell types, but only to other types of blood cells (see Figure 1, left column). They are one of many examples of adult stem cells, which are tissue-specific stem cells that are essential for organ maintenance and repair in the adult body. Muscle, for instance, also possesses a population of adult stem cells. Called satellite cells, these muscle cells are unipotent, as they can give rise to just one cell type, muscle cells.

Therefore, the foundations of stem cell research lie not with the famous (or infamous) human embryonic stem cells, but with HSCs, which have been used in human therapy (such as bone marrow transplants) for decades. Still, what ultimately fueled the enormous impact that the stem cell research field has today is undoubtedly the isolation and generation of pluripotent stem cells, which will be the main focus of the remainder of the text.

Figure 1: Varying degrees of stem cell potency. Left: The fertilized egg (totipotent) develops into a 300-cell structure, the blastocyst, which contains embryonic stem cells (ES cells) at the inner cell mass (ICM). ES cells are pluripotent and can thus give rise to all cell types in our body, including adult stem cells, which range from multipotent to unipotent. Right: An alternative route to obtain pluripotent stem cells is the generation of induced pluripotent stem cells (iPS cells) from patients. Cell types obtained by differentiation of either ES cell (Left) or iPS cells (Right) can then be studied in the dish or used for transplantation into patients. Figure drawn by Hannah Somhegyi.

Martin Evans (Nobel Prize, 2007) and Matt Kauffman were the first to identify, isolate and successfully culture ES cells using mouse blastocysts in 1981 []. This discovery opened the doors to the creation of murine genetic models, which are mice that have had one or several of their genes deleted or otherwise modified to study their function in disease []. This is possible because scientists can modify the genome of a mouse in its ES cells and then inject those modified cells into mouse blastocysts. This means that when the blastocyst develops into an adult mouse, every cell its body will have the modification of interest.

The desire to use stem cells unique properties in medicine was greatly intensified when James Thomson and collaborators first isolated ES cells from human blastocysts []. For the first time, scientists could, in theory, generate all the building blocks of our body in unlimited amounts. It was possible to have cell types for testing new therapeutics and perhaps even new transplantation methods that were previously not possible. Yet, destroying human embryos to isolate cells presented ethical and technical hurdles. How could one circumvent that procedure? Sir John Gurdon showed in the early 1960s that, contrary to the prevalent belief back then, cells are not locked in their differentiation state and can be reverted to a more primitive state with a higher developmental potential. He demonstrated this principle by injecting the nucleus of a differentiated frog cell into an egg cell from which the nucleus had been removed. (This is commonly known as reproductive cloning, which was used to generate Dolly the Sheep.) When allowed to develop, this egg gave rise to a fertile adult frog, proving that differentiated cells retain the information required to give rise to all cell types in the body. More than forty years later, Shinya Yamanaka and colleagues shocked the world when they were able to convert skin cells called fibroblasts into pluripotent stem cells by altering the expression of just four genes []. This represented the birth of induced pluripotent stem cells, or iPS cells (see Figure 1, right column). The enormous importance of these findings is hard to overstate, and is perhaps best illustrated by the fact that, merely six years later, Gurdon and Yamanaka shared the Nobel Prize in Physiology or Medicine 2012 [].

Since the generation of iPS cells was first reported, the stem cell eld has expanded at an unparalleled pace. Today, these cells are the hope of personalized medicine, as they allow one to capture the unique genome of each individual in a cell type that can be used to generate, in principle, all cell types in our body, as illustrated on the right panel of Figure 1. The replacement of diseased tissues or organs without facing the barrier of immune rejection due to donor incompatibility thus becomes approachable in this era of iPS cells and is the object of intense research [].

The first proof-of-principle study showing that iPS cells can potentially be used to correct genetic diseases was carried out in the laboratory of Rudolf Jaenisch. In brief, tail tip cells from mice with a mutation causing sickle cell anemia were harvested and reprogrammed into iPS cells. The mutation was then corrected in these iPS cells, which were then differentiated into blood progenitor cells and transplanted back into the original mice, curing them []. Even though iPS cells have been found not to completely match ES cells in some instances, detailed studies have failed to find consistent differences between iPS and ES cells []. This similarity, together with the constant improvements in the efficiency and robustness of generating iPS cells, provides bright prospects for the future of stem cell research and stem cell-based treatments for degenerative diseases unapproachable with more conventional methods.

Leonardo M. R. Ferreira is a graduate student in Harvard Universitys Department of Molecular and Cellular Biology

[] Stem Cell Basics: http://stemcells.nih.gov/info/basics/Pages/Default.aspx

[] Becker, A. J., McCulloch, E.A., Till, J.E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 1963. 197: 452-4

[] Siminovitch, L., McCulloch, E.A., Till, J.E. The distribution of colony-forming cells among spleen colonies. J Cell Comp Physiol 1963, 62(3): 327-336

[] Evans, M. J. and Kaufman, M. Establishment in culture of pluripotential stem cells from mouse embryos. Nature 1981, 292: 151156

[] Simmons, D. The Use of Animal Models in Studying Genetic Disease: Transgenesis and Induced Mutation. Nature Education 2008,1(1):70

[] Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282(5391): 1145-1147

[] Takahashi, K. and Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006. 126(4): 663-76

[] The Nobel Prize in Physiology or Medicine 2012:

[] Ferreira, L.M.R. and Mostajo-Radji, M.A. How induced pluripotent stem cells are redefining personalized medicine. Gene 2013. 520(1): 1-6 [] Hanna J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007. 318: 1920-1923

[] Yee,J.Turning Somatic Cells into Pluripotent Stem Cells.Nature Education 2010.3(9):25

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Stem cells: a brief history and outlook - Science in the News

Recommendation and review posted by Bethany Smith

Sometimes patients or my students ask me, What are the best stem cells? what information are they looking for?

I think they often are looking for the most powerful stem cells so perhaps they should be asking, What are totipotent stem cells?

Other times it seems what patients specifically want to know is what might be the best stem cells for their particular condition. The answer to that is, of course, going to depend on many factors. Im a long-time stem cell biologist so I can give them that perspective, but this should be something they discuss primarily with their physician

Todays post focuses on the question of what totipotent cells are all about and addresses more specific questions about them, including why so far there seem to be fewer clinical applications for them as compared to most other stem cell types.

Every year I give a lecture here at UC Davis School of Medicine for my medical students about stem cells. Some students seem especially fascinated by totipotent stem cells. Their interest probably is piqued because these are the most powerful cells. For example, recently a student asked me, Professor Knoepfler, are there any types of cells that totipotent stem cells cannot make?

As their name implies, totipotent stem cells are entirely potent or all-powerful from a cellular perspective. What that means is that these cells can make any other cells in the developing body in utero as well as the special cells and tissues needed during development. Those latter structures include placenta and umbilical cord.

For example, the classic kind of totipotent cell is the fertilized egg, also called a zygote. In the animal world, a newly pregnant bear has a zygote that will develop in its uterus that is totipotent. That bears zygote can make the actual new eventual baby bear including all of the several hundred kinds of bear cells and also the placenta and umbilical cord that the fetal bear will need in utero. The same goes for a totipotent human zygote. Also the zygote of a dog, cat, and so on.

You can see examples of real human totipotent stem cells in the image above of early human embryos at the 2- and 4-cell stages at the top of the figure. This material is excerpted from my book on stem cells, Stem Cells: An Insiders Guide.

Interestingly, as normal early embryo development proceeds and the fertilized egg/zygote goes from just being that one cell to divide to make 2 cells and 4 cells and then 8 cells, it is thought that all of the cells are still totipotent. What this means is that if, for example, an 8-cell human embryo for whatever reason breaks into 2 pieces of 3 and 5 cells or 1 and 7 cells, in many cases those separate totipotent cells will go on to make 2 separate embryos and ultimately babies. Congrats, you have twins. Each twin in that case can also develop their own umbilical cord and placenta too, although they sometimes share. This is all possible because these very early embryonic cells are totipotent.

After the 8-cell stage or so, the embryonic cells start to lose their totipotency and become either multipotent (can make only a few types of cells) or pluripotent stem cells. The latter are the second most powerful stem cells so lets briefly talk about them next.

Pluripotent stem cells are almost as flexible as those with totipotency, but not quite. See video above. The pluripotent cells inside a developing early embryo of a specific species can make all the cells that will become the actual body of a person, a bear, or many other animals, again depending on which animal is involved. These pluripotent cells cannot, however, make the placenta or umbilical cord. This one thing that they cannot do is what makes them different than totipotent cells.

Pluripotent stem cells include some of the most well known kinds of stem cells out there including embryonic stem cells (ES cells) and induced pluripotent stem cells, also known as IPS cells.

Pluripotent stem cells are often grown in labs and differentiated into a wide variety of other types of more specialized cells such as neurons, muscle cells including beating heart muscle (see video below), lung cells and more. Some have claimed that certain IPS cells can be totipotent but that is still being debated.

Both ES cells and IPS cells can also be made into what are called organoids, which are miniature versions of normal organs. For instance, my lab makes brain organoids regularly from IPS cells. Organoids are a very powerful technology in many ways so as being a way to find new drugs for specific diseases.

I have not heard yet of specific clinical applications for these most powerful stem cells. On the global clinical trial database Clinicaltrials.gov I found just a single trial that mentions the word totipotent and it isnt related to using such cells as a treatment.

Most of the clinical potential seems to be focused on adult stem cells as well as IPS cells and ES cells. One could imagine that totipotent stem cells will be useful for research on human development and potentially infertility.

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What are totipotent stem cells & what can they do? - The Niche

Recommendation and review posted by Bethany Smith

William W. Li MD writes in his book Eat to Beat Disease, Your immune cells are regenerated every seven days, so if your stem cells disappeared, youd likely die of an infection soon after. However, you can increase your stem cells by taking in the right foods.

We develop from stem cells. When the fathers sperm meets the mothers egg, a fertilized egg is formed. It continues to divide and by day three to five develops into an embryoconsisting of about 150 stem cells in the mothers uterus. Later, these stem cells in the embryo continue to split and form various tissues and organs in the human body. There are more than two hundred different kinds of cells in the human body, all of which grow from stem cells.

Stem cells are not only present at the embryonic development stage. When babies are born, they carry a large number of stem cells within their bodies. The average person has about 37.2 trillion cells, including about 750 million stem cells, which account for 0.002 percent of the total cells (Page 27, Eat to Beat Disease).These stem cells are stored in various parts of the body, ready to regenerate or repair body tissues and organs.

Dr. William Li, the author of Eat to Beat Disease, president of the Angiogenesis Foundation and a Harvard-trained medical doctor, elaborated on the role of stem cells in an interview with The Epoch Times. Li said stem cells are mainly stored in the bone marrow, though also found in the bodys fat, skin, hair follicles, and even in the heart. He made an analogy: The human body retains and dispatches stem cells just like we keep unused paint in the garage during renovation, which is ready for use if necessary, say, for wall repair someday.

As all human tissues and organs get renewed constantly, stem cells play a key role in this process. Specifically, we need them to produce new skin to replace damaged skin cells; and to replace damaged cells on the surface of the intestine. Besides, hematopoietic stem cells divide and replace those blood cells that are damaged while operating in the circulatory system. They, too, evolve into types of white and red blood cells, and more.

Interestingly, our small intestine is renewed every two to four days; our lungs and stomach every eight days; our skin every two weeks; our red blood cells every four months; our fat cells every eight years; and our skeleton every ten years. Dr. Li cited an example: The bodys immune cells regenerate every seven days. Therefore, if a persons relevant stem cells disappear, he or she could die soon from an infection (Page 26, Eat to Beat Disease).

In addition, he quoted a Japanese story of nuclear radiation to highlight the critical life-supporting role of stem cells in his book. During the Second World War, the atomic bombardments in the cities of Hiroshima and Nagasaki caused about 200,000 deaths. Afterward, a second wave of deaths hit certain survivors because the ability of their bone marrow to make stem cells had been destroyed due to exposure to radiation. Further, in cancer treatment, chemotherapy and radiotherapy affect the survival of stem cells while destroying cancer cells, putting patients in tremendous pain and challenges (page 26, Eat to Beat Disease).

The human body is born with mechanisms that collaborate seamlessly and automatically to keep life going.

Stem cells come into play when we need to repair cells that are damaged due to various diseases and injuries or replace dysfunctional cells. Figuratively, stem cells are sentinels in the body that are always watching out for health needs and will at times appear at designated locations in preparation for rescue operations.

Dr. Li added that a damaged organ or site in need of repair releases a certain protein that acts as a messenger, calling on stem cells stored in the bone marrow. Then, the cells will respond to the call by leaving the bone marrow and entering the bloodstream. This scenario is almost like a group of bees swarming out of their hive. Together with the blood, stem cells flow to the injured tissue and land at their precise destination. Upon arriving, they begin to divide or transform themselves to regenerate organ or tissue cells.

As is well known, the liver is regenerative. It is the repair and regeneration function of stem cells that explains exactly why the liver can grow back into its original status, even if up to 75 percent of it is removed during surgery.

Likewise, our heart depends on stem cells to keep regenerating constantly, though the rebirth rate is affected by age. A 20-year-old gets about one percent of his or her heart cells renewed every year. However, this rate slows down as he or she gets older. At 75, that person gets only 0.3 percent of the heart cells renewed each year.

Reading that, you may wonder: Will stem cells eventually be depleted as they keep flowing out of the bone marrow? Dr. Lis answer is, Stem cells are capable of regenerating themselves and replenishing their stores in the bone marrow.

Although stem cells in healthy people are equipped with self-replication and replenishment mechanisms, Dr. Li emphasized that there are three scenarios that impair their regenerative and repairing capacity, directly affecting the quality of a persons life.

When smokers inhale cigarette smoke, that leads to a lack of oxygen in the body, which will recruit stem cells into the bloodstream. Habitual smoking keeps consuming the stem cells stored in the bone marrow. A study has shown that the remaining stem cells in smokers bodies have a 75 percent drop in their self-reproduction ability and a 38 percent reduction in their involvement in regeneration. Besides active smoking, Dr. Li added, passive inhalation of secondhand smoke and exposure to heavily polluted air can be equally harmful to stem cells.

Addiction to alcohol kills stem cells. Like smoking, drinking alcohol causes stem cells to be constantly pulled out of the bone marrow into the circulatory system. Meanwhile, stem cells become damaged, negatively affecting their regeneration abilities, according to Dr, Li. Furthermore, drinking alcohol impairs the activity of stem cells in the brain, which in turn affects the hippocampusresponsible for short- and long-term memory.

Both hyperlipidemia and hyperglycemia impair stem cells. Dr. Li says in his bookthat bad cholesterol in the blood, known as low-density lipoprotein (LDL), damages liver cells while good cholesterol, known as high-density lipoprotein (HDL), delays the death of endothelial progenitor cellsa type of stem cell in the blood that maintains the health of blood vessels and repairs their inner layers.

Additionally, diabetes is a stem cell killer. Diabetics are likely to have 47 percent fewer stem cells than normal, with the remaining part of stem cells unable to function properly. This is because hyperglycemia affects stem cell replication and migration, as well as the secretion of survival factors.

Dr. Li also mentioned that high levels of stress and high salt levels in the blood also harm stem cells.

Dr. Li gives advice on how to protect the activity of stem cells in the body and actively mobilize them to repair the body from a dietary perspective. Human experiments have confirmed the following foods, which can increase the number of stem cells.

Dark chocolate contains flavanols that have biological properties. Researchers at the University of California recruited patients with coronary artery disease in a 30-day controlled trial. One group drank hot chocolate low in flavanols (only nine mg per serving) twice a day, and the other group drank hot chocolate high in flavanols (containing 375 mg per serving) twice a day. The results were surprising: the group with high-level flavanol had twice as many stem cells in their blood as that with low-level flavanol, and the formers blood flow improved twice as much as the latter.

A team of Italian researchers divided patients who had mild to moderate hypertension but did not receive medication into two groups. Group A drank plain black tea without sugar and milk twice a day while group B drank other beverages twice a day. One week later, blood tests showed the number of endothelial progenitor cells in the blood in the black-tea group rose by 56 percent, with an improved ability of blood vessel widening.

A Mediterranean diet rich in virgin olive oil is effective in boosting stem cells. A 4-week control study published in The American Journal of Clinical Nutrition showed that compared to those on a diet high in saturated fat or a diet low in fat but high in carbohydrates, those on a Mediterranean diet rich in virgin olive oil showed a significant doubling in their endothelial progenitor cell count in the blood.

Flora Zhao is a health reporter for The Epoch Times. Have a tip? Email her at: flora.zhao@epochtimes.nyc

Health 1+1 is the most authoritative Chinese medical and health information platform overseas. Every Tuesday to Saturday from 9:00 a.m. to 10:00 a.m. EST on TV and online, the program covers the latest on the coronavirus, prevention, treatment, scientific research and policy, as well as cancer, chronic illness, emotional and spiritual health, immunity, health insurance, and other aspects to provide people with reliable and considerate care and help. Online: EpochTimes.com/HealthTV: NTDTV.com/live

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Certain Foods Discovered to Increase Stem Cells, Cell Regeneration

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Skin cells are the basic building blocks of the skin; a large, complex organ forms a protective barrier between our insides and the external environment. The most common type of skin cell is the keratinocyte, whose primary function is to form a tough, waterproof layer against UV radiation, harmful chemicals, and infectious agents.

However, the skin also contains highly specialized cells with important immunological, photoprotective, and sensory functions. The term skin cell, therefore, may refer to any of the four major types of cells found in the epidermis (or outer layer) of the skin.

The skin is the largest organ of the human body and has a range of vital functions in supporting survival. The primary function of the skin is to form a physical barrier between the internal environment of an organism and the outside world. This protects internal organs and structures from injury and infection.

The skin also helps to maintain homeostasis by preventing water loss and regulating body temperature. It protects organisms from the damaging effects of UV light and helps to produce vitamin D when exposed to the sun. Finally, the skin functions as a sensory organ, allowing us to perceive touch, temperature changes, and pain.

The skin can perform all of these functions thanks to the highly specialized cells that make up the epidermis (the outermost layer of the skin).

The skin consists of three major layers; the epidermis, the dermis, and the hypodermis (AKA the subcutaneous layer).

The epidermis is the outermost layer of the skin. This waterproof barrier protects the underlying skin layers and other internal structures from injury, UV damage, harmful chemicals, and infections by pathogens such as bacteria, viruses, and fungi. The thickness of the epidermis varies between different parts of the body. In the thin, delicate skin of the eyelids, the epidermis is only around 0.5 mm thick, whereas the more resilient skin of the palms and feet is about 1.5 mm thick.

The dermis is found directly beneath the epidermis and is the thickest of the three skin layers. This layer contains a complex network of specialized structures, including blood vessels, lymph vessels, sweat glands, hair follicles, sebaceous glands, and nerve endings. It also contains collagen and elastin, which are structural proteins that make skin strong and flexible. The main functions of the dermis are to deliver oxygen and nutrients to the epidermis and to help regulate body temperature.

The hypodermis (or subcutaneous layer) is the fatty, innermost layer of the skin. It consists mainly of fat cells and functions as an insulating layer that helps to regulate internal body temperature. The hypodermis also acts as a shock absorber that protects the internal organs from injury.

The term skin cell may refer to any of the four main types of cells found in the epidermis. These are keratinocytes, melanocytes, Langerhans cells, and Merkel cells. Each type of skin cell has a unique role that contributes to the overall structure and function of the skin.

Keratinocytes are the most abundant type of skin cell found in the epidermis and account for around 90-95% of the epidermal cells.

They produce and store a protein called keratin, a structural protein that makes skin, hair, and nails tough and waterproof. The main function of the keratinocytes is to form a strong barrier against pathogens, UV radiation, and harmful chemicals, while also minimizing the loss of water and heat from the body.

Keratinocytes originate from stem cells in the deepest layer of the epidermis (the basal layer) and are pushed up through the layers of the epidermis as new cells are produced. As they migrate upwards, keratinocytes differentiate and undergo structural and functional changes.

The stratum basal (or basal layer) is where keratinocytes are produced by mitosis. Cells in this layer of the epidermis may also be referred to as basal cells. As new cells are continually produced, older cells are pushed up into the next layer of the epidermis; the stratum spinosum.

In the stratum spinosum (or squamous cell layer), keratinocytes take on a spiky appearance and are known as spinous cells or prickle cells. The main function of this epidermal layer is to maintain the strength and flexibility of the skin.

Next, the keratinocytes migrate to the stratum granulosum. Cells in this layer are highly keratinized and have a granular appearance. As they move closer to the surface of the skin, keratinocytes begin to flatten and dry out.

By the time keratinocytes enter the stratum lucidum (AKA the clear layer), they have flattened and died, thanks to their increasing distance from the nutrient-rich blood supply of the stratum basal. The stratum corneum (the outermost layer of the epidermis) is composed of 10 30 layers of dead keratinocytes that are constantly shed from the skin. Keratinocytes of the stratum corneum may also be referred to as corneocytes.

Melanocytes are another major type of skin cell and comprise 5-10% of skin cells in the basal layer of the epidermis.

The main function of melanocytes is to produce melanin, which is the pigment that gives skin and hair its color. Melanin protects skin cells against harmful UV radiation and is produced as a response to sun exposure. In cases of continuous sun exposure, melanin will accumulate in the skin and cause it to become darker i.e., a suntan develops.

Langerhans cells are immune cells of the epidermis and play an essential role in protecting the skin against pathogens. They are found throughout the epidermis but are most concentrated in the stratum spinosum.

Langerhans cells are antigen-presenting cells and, upon encountering a foreign pathogen, will engulf and digest it into protein fragments. Some of these fragments are displayed on the surface of the Langerhans cell as part of its MHCI complex and are presented to nave T cells in the lymph nodes. The T cells are activated to launch an adaptive immune response, and effector T cells are deployed to find and destroy the invading pathogen.

Merkel cells are found in the basal layer of the epidermis and are especially concentrated in the palms, finger pads, feet, and undersides of the toes. They are positioned very close to sensory nerve endings and are thought to function as touch-sensitive cells. Merkel cells allow us to perceive sensory information (such as touch, pressure, and texture) from our external environment.

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Skin Cell - The Definitive Guide | Biology Dictionary

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Cryonics is the practice of freezing the body at subzero temperatures, with the hope that future technology will be able to bring it back to life. Many companies have begun offering this service, but there is little to no evidence that cryo-preserved bodies can be revived.

Who doesnt want to live as long as they can? If given the chance, some people would want to live forever!

Humans put a lot of effort into extending our individual stays on this planet. Eating greens, running, intermittent fasting, juice cleansing, turning into a teetotaler the list goes on and on. Unless you live in one of the five blue zones on Earth, where people tend to live the longest, hitting the century mark in life seems to be one hell of a challenging task. No matter how careful you are, disease will eventually come knocking at the door.

However, what if theres a way to cheat nature? What is there was a path to immortality?

For those terrified of aging and death, cryonics might be the answer. Cryonics claims to be the key to immortality. It can help you resume your life after rising from the dead, but not in the way vampires do.

So what is the science behind cryonics? Is it a sham or a scientific breakthrough?

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Imagine that youre dying due to a disease with no cure. Doctors are working to find a cure, but you just dont have enough time before it ends your life. What if you could pause the process of dying until medical research caught up with your disease and a cure became available?

This is where cryonics appears as a ray of hope for your dying body. Cryonics is the practice of freezing the body at subzero temperatures, in the hopes that future technology can bring it back to life. It sounds like a good concept for a sci-fi movie, doesnt it? Thats because movies like Passenger and Vanilla Sky have played with this very appealing idea.

Given its experimental nature and the advanced equipment required for the process, it probably wont come as a surprise that cryopreservation can cost a fortune. Then again, whats the use of all that money if it cant buy you a life?

Assuming that you have the millions of dollars required to extend your life after death, how exactly will your body be frozen?

Once youve been declared legally dead, cryopreservation can begin.

To keep the brain tissues protected, blood circulation and breathing are temporarily restored by CPR and an oxygen mask until the specialized medications can be injected into the system. A medical team then cools the body by placing it in an ice water bath, and injecting anticoagulants to prevent the blood from clotting. Within 24 hours of death, the body is taken to the cryopreservation center where the body is safely preserved.

When you fill the ice tray with water and keep it in the freezer, you have probably observed that water expands upon freezing. This is because the water molecules form a hexagonal crystalline structure when frozen, which takes up more space than liquid water.

The average human body is made of 60% water. If not frozen correctly, the water present in our cells would turn into ice. Ice expands in volume and forms crystal lattices, putting pressure on cell walls and blood vessels, which can cause the cells and tissues to crack open. If the ultimate goal of cryonics is to restore your body to a healthy living condition at some time in the future, a body full of ruptured cells wont be very helpful. This is where a process known as Vitrification comes to the rescue. Vitrification allows the body to be frozen in time.

Vitrification is the process of turning a substance into glass, a non-crystalline amorphous solid. The process is done by introducing anti-freeze chemicals known as cryoprotectants into the bloodstream. Glycerol and dimethyl sulfoxide (DMSO) are common cryoprotectants that are used before starting the freezing process.

Cryoprotectants prevent the formation of ice crystals by increasing intracellular solute concentration. This allows the water molecules to be locked in place without turning into ice crystals, even after being frozen below -100 C. No ice formation means no structural damage to the bodys cells. However, with the increase in the concentration of cryoprotectants in the body, the chances of toxicity also increase.

Once your body has been safely vitrified, it will be lowered into a cryopreservation tank, i.e., your new icy home. For the foreseeable future, your body will be kept at a toasty -196C with the help of liquid nitrogen. This will protect the body from any deterioration for potentially thousands of years so to speak.

And then?

Wait and hope that science finds a way to bring you back.

The legitimacy of cryonics is one of the main ethical concerns for practitioners, opponents, and potential people popsicles. There is no proof or guarantee that the body can bounce back to health after being frozen for years. Whos to say that resurrection after being cryogenically frozen is nothing less than a false hope? Freezing your body in the hopes of scientific advancement that will help resume life sounds a lot like science fiction.

Some argue that cryonics may also promote a trend of euthanasia, as people might prefer cryopreservation while their body remains untouched by disease and old age.

Lets consider a scenario where we find a way to bring a person back to a healthy living condition. Will the cryopreserved person retain their original personality and identity? Theres no guarantee that cryopreservation wont permanently alter brain function. Additionally, after waking up after thousands of years, people would find themselves alone, without any family or friends. The prospect of being alone can be frightening for some. Another main concern would be that such resurrected beings would further add to the population on Earth.

A century ago, a trip to outer space was an unimaginable idea. Now, astronauts frequently fly to the International Space Station, so clearly, no one can truly know what the future holds. There is a possibility that coming back to life after being cryogenically frozen for years is the real deal. Or maybe cryonics is nothing but a fantastic notion.

However, there are a few possibilities that would make cryonically freezing someone a failure. If the body is damaged before or after cryopreservation, it will be impossible to revive the brain function of that person. The most disheartening possibility, of course, is that even in the future, science may never be able to fully revive a cryopreserved body.

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Is It Possible To Freeze People And Bring Them Back To Life?

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On December 15, 1966, animation legend Walt Disney died from complications of lung cancer, for which he had undergone surgery just over a month earlier. A private funeral was held the next day, and on December 17, his body was cremated and interred at Forest Lawn Memorial Park in Glendale, California. But while Disney undoubtedly lives on through the legacy of the beloved feature films and theme parks that comprise much of his lifes work, shortly after his death, a rumor began to circulate that he might be living on in a more literal sense as well with his body suspended in a frozen state and buried deep beneath the Pirates of the Caribbean ride at Disneyland in Anaheim, California, awaiting the day when medical technology would be advanced enough to reanimate the animator.

Over the years, proponents of this seemingly absurd rumor have cited the secrecy surrounding Disneys death and burial as evidence of its veracity. They claim that news of his passing was intentionally delayed in order to give his handlers time to place his body in cryonic suspension and that both his funeral and the actual location of his burial plot have been kept secret as a means of further concealing the truth of his interment.

Disneys lifelong interest in the future, projects such as his EPCOT Center (Experimental Prototype Community of Tomorrow) and the technical innovations for which he was known throughout his career would no doubt have lent the rumor a certain air of truth, while a Time magazine article about the cryonic freezing of a 73-year-old psychology professor also lent its weight.

The assertions of two separate biographies of DisneyLeonard Moselys Disneys World (1986)and Marc Eliots Walt Disney: Hollywoods Dark Prince(1993)which claimed that an obsession with death led Disney to an interest in cryonics, surely did their part to perpetuate it through the years as well.

In a 1972 biography about her father, Disney's daughter Diane wrote that she doubted he had even heard of cryonics.

Photo: United Artists/Photofest

The exact origins of the rumor are uncertain, but it first appeared in print in a 1969 Ici Paris article in which a Disney executive attributed it to a group of disgruntled animators seeking to have a laugh at their late taskmaster employers expense.

Disneys daughter, Diane, wrote in a 1972 biography about her famous father that she doubted her father had even heard of cryonics. It has been further discredited by those pointing to the existence of signed legal documents that indicate Disney was in fact cremated and that his remains are interred in a marked plot (for which his estate paid $40,000) at Forest Lawn, the exact location of which is a matter of public record.

Further, by all accounts, Disney was known to be a very private man in life, making the quiet circumstances of his cremation and burial far from suspect, and the assertions in Moselys and Eliots biographies have been widely rejected as unfounded.

Yet despite the apparent lack of any credible evidence supporting a connection between it and Disney, the existence of cryonics is very much a reality. Since 1964, when Robert Ettinger published a work discussing the plausibility of freezing human beings for the purpose of bringing them back to life, a significant cryonics industry has developed in the United States.

Today,companies such as Suspended Animation Inc.,Cryonics Institute and Alcor Life Extension Foundation offer their clients the opportunity to have their bodies placed in a large metal tank in a state of deep freeze known as cryostasis, for the purpose of being restored to life and complete physical and mental health at a theoretical point in the future when medical science is advanced enough to do so.

According to reports, there are hundreds of people being kept in cryostasis at facilities around the country and thousands more that have already made arrangements for their own preservation. Following his death in 2004, baseball legend Ted Williams became the highest-profile person to date to be placed in cryostasis.

Cryonics is not without its detractors, however. Its science has been largely dismissed as fantastical. Still, its the futuristic stuff of science fiction that maybe even Disney himself would have appreciated.

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Is Walt Disney's Body Frozen? - Biography

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What is genetic testing?

Genetic testing is the use of medical tests to look for certain mutations (changes) in a persons genes. Many types of genetic tests are used today, and more are being developed.

Genetic testing can be used in many ways, but here well focus on how it is used to look for gene changes that are linked to cancer. (To learn about the role of genes and how mutations can lead to cancer, seeGenes and Cancer.)

Predictive genetic testing is a type of testing used to look for inherited gene mutations that might put a person at higher risk of getting certain kinds of cancer. This type of testing might be suggested for:

Most people (even people with cancer) do not need this type of genetic testing. Its usually done when family history suggests that a cancer may be inherited (see below) or if cancer is diagnosed at an uncommonly young age.

Genetic counseling and testing may be recommended for people who have hadcertain cancers or certain patterns of cancer in their family. If you have any of the following, you might consider talking to a genetic counselor about genetic testing:

If you are concerned about a pattern of cancer in your family, cancer youve had in the past, or other cancer risk factors, you may want to talk to a health care provider about whether genetic counseling and testing might be a good option for you.

You need to know your family history and what kinds of tests are available. For some types of cancer, no known mutations have been linked to an increased risk.

For more information on the types of cancer that may be linked to inherited genes,see Family Cancer Syndromes.

Genetic counseling gives you information that you and your family can use to make decisions about whether to get genetic testing (see below).

Genetic counselors have special training in the field of genetic counseling. Most are board-certified, and some might have a license depending on the rules in their state. Some doctors, advanced practice oncology nurses, social workers, and other health professionals may also provide genetic counseling, although they might have different levels of training in this field. If you are offered genetic counseling, its fair to ask about their training in this area.

Before and after genetic testing, genetic counseling can help you understand what your test results might mean, your risk of developing cancer, and what you can do about this risk. It is your decision to have testing and what steps you take after.

Its important to find out how useful genetic testing might be for you before you do it. Talk to your health care provider and plan on getting genetic counseling before the actual test. This will help you know what to expect. Yourcounselor can also tell you about the risks and benefits of the test, what the results might mean, and what your options are.

Your health care provider can refer you to a genetic counselor in your area, or you can find a list of certified genetic counselors on the website of the National Society of Genetic Counselors.

To learn more, see What Should I Know Before Getting Genetic Testing?

Sometimes after a person has been diagnosed with cancer, the doctor will order tests on a sample of cancer cells to look for certain gene or protein changes. These tests can sometimes give information on a persons outlook (prognosis), and they might also help tell if certain types of treatment may be useful.

These types of tests look for acquired gene changesonlyin the cancer cells. These tests are not the same as the tests used to find out about inherited cancer risk.

For more about this kind of testing and its use in cancer treatment, see Biomarker Tests and Cancer Treatment.

Some tests that look for gene changes can be bought without needing a doctors order. For this type of testing, you purchase a test kit and send a sample of your DNA (often from saliva) to a lab for testing.

If you are considering using a home-based genetic test (also known as a direct-to-consumer genetic test), you need to know what its testing for, what it can (and cant) tell you, and how reliable the test is.

Home-based tests do not provide information on a persons overall risk of developing any type of cancer. Sometimes these tests can sound much more helpful and certain than they have been proven to be. It may sound like the test will provide an answer to your specific health concern, such as your risk of hereditary cancer, but the test may not be able to answer that question completely. For example, a test may look for mutations in a certain gene, but it might not test for all of the possible mutations. So a negative test result, even if accurate, may miss the bigger picture regarding your cancer risk and what you can do to manage it. And you might not be provided with the important context about the test results that a genetic counselor could provide.

Home-based genetic tests should not be used instead ofcancer screeningorgenetic counselingthat may be recommended by a medical professional based on your individual risk for cancer.Always consult with your doctor if you are considering or have questions aboutgenetic testing. Trained genetic counselors can help you know whatto expect from your test results.

Link:
Understanding Genetic Testing for Cancer Risk

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Amniocentesis: A procedure in which amniotic fluid and cells are taken from the uterus for testing. The procedure uses a needle to withdraw fluid and cells from the sac that holds the fetus.

Amniotic Fluid: Fluid in the sac that holds the fetus.

Aneuploidy: Having an abnormal number of chromosomes.

Cells: The smallest units of a structure in the body. Cells are the building blocks for all parts of the body.

Chorionic Villus Sampling (CVS): A procedure in which a small sample of cells is taken from the placenta and tested.

Chromosomes: Structures that are located inside each cell in the body. They contain the genes that determine a person's physical makeup.

Cystic Fibrosis: An inherited disorder that causes problems with breathing and digestion.

Diagnostic Tests: Tests that look for a disease or cause of a disease.

DNA: The genetic material that is passed down from parent to child. DNA is packaged in structures called chromosomes.

Embryo: The stage of development that starts at fertilization (joining of an egg and sperm) and lasts up to 8 weeks.

Fetus: The stage of human development beyond 8 completed weeks after fertilization.

Fluorescence In Situ Hybridization (FISH): A screening test for common chromosome problems. The test is done using a tissue sample from an amniocentesis or chorionic villus test.

Genes: Segments of DNA that contain instructions for the development of a person's physical traits and control of the processes in the body. The gene is the basic unit of heredity and can be passed from parent to child.

Genetic Counselor: A health care professional with special training in genetics who can provide expert advice about genetic disorders and prenatal testing.

Genetic Disorders: Disorders caused by a change in genes or chromosomes.

Hospice Care: Care that focuses on comfort for people who have an illness that will lead to death.

In Vitro Fertilization (IVF): A procedure in which an egg is removed from a woman's ovary, fertilized in a laboratory with the man's sperm, and then transferred to the woman's uterus to achieve a pregnancy.

Karyotype: An image of a person's chromosomes, arranged in order of size.

Microarray: A technology that examines all of a person's genes to look for certain genetic disorders or abnormalities. Microarray technology can find very small genetic changes that can be missed by the routine genetic tests.

Monosomy: A condition in which there is a missing chromosome.

Mutations: Changes in a gene that can be passed on from parent to child.

ObstetricianGynecologist (Ob-Gyn): A doctor with special training and education in women's health.

Placenta: An organ that provides nutrients to and takes waste away from the fetus.

Preimplantation Genetic Diagnosis: A type of genetic testing that can be done during in vitro fertilization. Tests are done on the fertilized egg before it is transferred to the uterus.

Screening Tests: Tests that look for possible signs of disease in people who do not have signs or symptoms.

Sickle Cell Disease: An inherited disorder in which red blood cells have a crescent shape, which causes chronic anemia and episodes of pain.

TaySachs Disease: An inherited disorder that causes intellectual disability, blindness, seizures, and death, usually by age 5.

Trisomy: A condition in which there is an extra chromosome.

Ultrasound Exam: A test in which sound waves are used to examine inner parts of the body. During pregnancy, ultrasound can be used to check the fetus.

Uterus: A muscular organ in the female pelvis. During pregnancy, this organ holds and nourishes the fetus. Also called the womb.

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Prenatal Genetic Diagnostic Tests | ACOG

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Continuing Education Activity

DiGeorge syndrome (DGS) is a congenital disorder with a broad phenotypic presentation, which results predominantly from the microdeletion of chromosome 22 at a location known as 22q11.2. This mutation results in the failure of appropriate development of the pharyngeal pouches, which are responsible for the embryologic development of the middle and external ear, maxilla, mandible, palatine tonsils, thyroid, parathyroids, thymus, aortic arch, and cardiac outflow tract. Features of DGS include cardiac anomalies, recurrent infections, abnormal facies, thymic hypoplasia or aplasia, cleft palate, developmental delay, and hypocalcemia. This activity outlines the diagnosis, evaluation, treatment, and management of patients with DGS, and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

Summarize the etiology of DiGeorge syndrome and its broad phenotypic presentation.

Review the evaluation of patients with DiGeorge syndrome.

Explain the treatment and management options available for DiGeorge syndrome.

Outline interprofessional team strategies for improving care coordination and communication to advance the care of patients with DiGeorge syndrome and improve outcomes.

DiGeorge Syndrome (DGS) is a combination of signs and symptoms caused bydefects in the development of structures derived from the pharyngeal archesduring embryogenesis. Features of DGSwere first described in 1828 but properly reported by Dr. Angelo DiGeorge in 1965, as a clinical trialthat included immunodeficiency, hypoparathyroidism, and congenital heart disease.[1]

DGS is one of several syndromes that has historically grouped under a bigger umbrella called 22q11 deletion syndromes, which include Shprintzen-Goldberg syndrome, velocardiofacial syndrome, Cayler cardiofacial syndrome, Sedlackova syndrome, conotruncal anomaly face syndrome, and DGS.Although the genetic etiology of these syndromes may be the same, varying phenotypeshas supported the use of different nomenclature in the past, which has led to confusion in diagnosing patients with DGS, which causes potentially catastrophic delays in diagnosis.[2] Current literature supports the use of the names of these syndromes interchangeably.

Features ofDGSincludean absent or hypoplastic thymus, cardiac abnormalities, hypocalcemia, and parathyroid hypoplasia (See "History and Physical" below). Perhaps, the most concerning characteristic of DGS is the lack of thymic tissue, becausethisis the organ responsible for T lymphocyte development.A complete absence of the thymus, though very rare and affecting less than 1% of patients with DGS, is associated with a form of severe combined immunodeficiency (SCID).T-cells are a differentiated type of white blood cellspecializingin certain immune functions: destroying cells that are infected or malignant,existing as an integralpart of the innate immune system by killing viruses (e.g., Killer T-cells), helping B-cells matureto produce immunoglobulins for strongeradaptive immunity (e.g. helper T-cells), etc. The degree of immunodeficiency of patients with DGS can present differently depending onthe extent of thymic hypoplasia.

Somepatients may have a mild to moderate immune deficiency, and the majority of patients have cardiac anomalies.Other features include palatal, renal, ocular, and gastrointestinal anomalies. Skeletal defects, psychiatric disease, and developmental delay are also of concern. There are different opinions about syndrome-related alterations in cognitive development, and a cognitive decline rather than an early onset intellectual disability is observable.[3] The particularities of the clinical presentation requires observation on an individual basis, with careful evaluation and interprofessional treatment throughout the patient's life.

About 90% of DGS cases are a result of a deletion in chromosome 22, more specifically on the long arm (q) at the 11.2 locus (22q11.2). Most of these mutations arise de novo with no genetic abnormalities noted in the genome of the parents of children with DGS.[1] Researchers have identified over 90 different genes at this locus, some of which they have studied in mouse models.The most studied of these genes isT-box transcription factor 1 (TBX1), which correlates with severe defects in the development of the heart, thymus, and parathyroid glands of mouse models. TBX1 also correlates with neuromicrovascular anomalies, which may be responsible for the behavioral and developmental abnormalities seen in DGS.[4][5]

Microdeletion of 22q11.2 is the most common microdeletion syndrome, affecting approximately 0.1% of fetuses.[6]The rate of 22q11.2 microdeletion in live births occurs at an estimated rate of 1 in 4000 to 6000.[1][7] There are several explanations for the variance in fetal versus live birth prevalence. Firstly, current evidence may not comprise a large enough population. Secondly, 22q11.2 microdeletions may produceembryonically lethal phenotypes, which was observable in animal studies.

The prevalence of 22q11.2 microdeletion may be more common than supported in literature due to several factors. Firstly, not every patient with this microdeletion presents with several craniofacial abnormalities and hence does notundergo genetic testing. African-American children, for example, may not have the craniofacial abnormalities characteristic of DGS in other races. Secondly, access to healthcare, specifically genetic testing, is not available to every individual that might have the microdeletion, regardless of the severity of craniofacial dysmorphism. Further population studies are therefore needed to fully understand the extent and spectrum of 22q11.2 microdeletions in different populations.[8]

DGS results from microdeletion of 22q11.2, which encodes over 90 genes. Patients with DGS display a broad array of phenotypes, and the most common findings include cardiac anomalies, hypocalcemia, and hypoplastic thymus.

On a genetic basis, TBX1 has correlations with the most prominent phenotypes characteristic of DGS. Failure in embryologic developmentof the pharyngeal pouches, which is driven by TBX1, leads to absence or hypoplasia of the thymus and parathyroid glands.Mouse and zebrafishTBX1 knockout models have been studied to understand the embryologic basis of this disease. In mice, for instance, the absence of TBX1 causes severe pharyngeal, cardiac, thymic, and parathyroid defects as well as a behavioral disturbance.[9]Moreover, zebrafish knockouts have demonstrated defects in the thymus and pharyngeal arches as well as malformation of the ears and thymus.[10]

A 22q11.2 knockout mouse model has also been studied, with findings pertinent for molecular and behavioral changes seen in Parkinson's disease, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia.[11][12]These findings, as well as the neuromicrovascular pathology found in TBX1 knockout mice, suggest a molecular basis for the psychiatric pathologies associated with DGS.[4][5]Of note, individuals affected bythissyndrome have a 30-fold increased risk of developing schizophrenia.

A detailed history and physical is vital in the diagnosis and assessment of DiGeorge syndrome. A broad spectrum of disease severity exists, and suspicion of DGS from history and physical can prompt further evaluation. Although most cases get diagnosed in theprenatal and pediatric periods, diagnosis can also occur in adulthood.Delay in motor development is a common presenting feature first recognized by parentswho notice delays in rolling over, sitting up, or other infant milestones.[13]These findings can be associated with delayed speech developmentand learning disabilities. Later in life, abnormal behavior in the setting of poor developmental history may be thechief presenting symptom of DGS.[1]

A detailed history mayrevealthefollowing:

Family history of diagnosed or suspected DGS

Abnormalgenetic testing results of family members

Delays in the achievement of developmental milestones

Behavioral disturbance

Cyanosis, exercise intolerance, or symptoms

Recurrent infections secondary to T-cell deficiency

Speech difficulty

Difficulty feeding and/or failure to thrive

Muscle spasms, twitching, tetany, seizure

An examination can reveal findings consistent with severalfeatures of DGS:

A complete cardiopulmonary evaluation can reveal murmurs, cyanosis, clubbing, or edema consistent withaortic arch anomalies, conotruncal defects (e.g., tetralogy of Fallot, truncus arteriosus, pulmonary atresia with ventricular septal defect, transposition of the great vessels, interrupted aortic arch), or tricuspid atresia.

A craniofacial examination may demonstrate abnormalities such as cleft palate, hypertelorism, ear anomalies, short down slanting palpebral fissures, short philtrum, and hypoplasia of the maxilla or mandible.

Recurrent sinopulmonary infections due to T cell deficiency as a result of thymic hypoplasia

Signs of hypocalcemia, including twitching and muscle spasm, may be evident as a result of parathyroid hypoplasia. Chvostek's and Trousseau's signs may be positive.

Delayed development, unusual behavior, or signs of psychiatric disorders may be observable.

A clinician makes a definitive diagnosis of DGS in individuals with amicrodeletion of chromosome 22 at the 22q11.2 locus. Classic evaluations of genetic abnormalities, such as trisomies, including the Giemsa banding technique, are incapable of revealing microdeletions. Microdeletions responsible for DGS are therefore detected by fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA),single nucleotide polymorphism (SNP) array, comparative genomic hybridization (CGH) microarray, or quantitative polymerase chain reaction (qPCR). The availability and cost of these techniques can delay diagnosis, particularly in resource-poor settings.

Patients diagnosed with or suspected of having DGS should undergo extensive evaluation, particularly if life-threatening cardiac or immunologic deficits are present. The following testsshould merit consideration:

Echocardiogram to evaluateconotruncal abnormalities

Complete blood count with differential

T and B Lymphocyte subset panels

Flow cytometry to assess T cell repertoire

Immunoglobulin levels

Vaccine titers for evaluation of response to vaccines

Serum ionized calcium and phosphorus levels

Parathyroid hormone level

Chest x-ray for thymic shadow evaluation

Renal ultrasound for possible renal and genitourinary defects

Serum creatinine

TSH

Testing for growth hormone deficiency

It is important to note that the broad spectrum of disease severity makesthe evaluationofDGS particularlychallenging. Cases involving significant cardiac, thymic, and craniofacial deficits are more easily recognizable than those lacking severe features. Implementation of advancing genomic studies and facial recognition technology in modern medicinemay assist in more effective diagnosis and evaluation of DGS patients.[14]

Treatment and management of DGS require intensive interprofessional care:

Fortunately, many patients with DGS have minor immunodeficiency, with preservation of T cell function despite decreased T cell production. Frequent follow-up with an immunologist experienced in treating primary immunodeficiencies is advisable. Immunodeficiency in neonates with complete DGS (cDGS) requires management with isolation, intravenous IgG,antibioticprophylaxis, and either thymic or hematopoietic cell transplant (HSCT).

Cardiac anomalies, if not diagnosed during the fetal ultrasound, may present shortly after birth as life-threatening cyanotic heart disease. Pediatric cardiothoracic surgery evaluation may be urgently required. Blood products, if necessary, should be irradiated, CMV negative, and leukocyte reduced to prevent transfusion-associated graft-versus-host disease. These measures also aim to reduce lung injury, particularly in surgical cases requiring cardiopulmonary bypass.

Cleft palate cases require evaluation by an otolaryngologist, plastic surgeon, or oral & maxillofacial surgeon with experience in surgical correction of palatal defects. Repair ofa cleft palate can improve feeding ability, speech, and reduce the incidence of sinopulmonary infections.

Hypocalcemia is manageable with calcium and vitamin D supplementation. Recombinant human PTH is an option in DGS patients refractory to standard therapy.

Autoimmune diseases are common in DGS patients, includingimmune thrombocytopenia(ITP), rheumatoid arthritis, autoimmune hemolytic anemia, Graves disease, and Hashimoto thyroiditis. DGS patientsshould be evaluated carefully for autoimmune symptoms regularly.

Audiologic evaluationis necessary for DGS patients experiencing difficulty with hearing. Children too young to express difficulty with hearing need assessment, particularly with a delay in cognitive and behavioral development.

Early intervention services arebeneficial for children with impaired cognitive and behavioral development.

Speech therapy isnecessary for difficulty with language secondary to craniofacial anomalies and/or cognitive impairment.

Genetic counseling is a reasonable consideration for parents of a child with DGS who desire more children, as well as for patients with DGS who may want to become parents. If a parent has the same mutation as an affected child, there is a 50% chance a new baby will also have DGS.

Advanced approaches for the management of children withcomplete DiGeorge anomaly

In the cDGS featuring no thymus function andbone marrow stem cells can not develop into T cells, childrenusually die by age 2 years due to severe infections. In this setting, the proposal is to T cellreplete HSCT. Nevertheless, because of the absence of thymus, thisstrategy can only obtain engraftment of post thymic T cells.[17]A multicenter survey on the outcome of HSCT showed a survival rate of 33% after matched unrelated donors and 60% in the case of matched sibling transplantations.[18] Recently, the FDA approved the thymus transplantation as standard care. This approach focuses on producingnaive T cellswith a broad T-cell receptor set. The procedure takes place using general anesthesia, and thymus tissue usually gets transplanted into the recipient subject's quadriceps. Studies indicateup to 75% of long-term survival but have described frequent autoimmune sequelae (e.g., autoimmune hemolysis, thyroiditis, thrombocytopenia, enteropathy, and neutropenia) in survivors.[19]

All patient findings that are part ofDiGeorge syndrome can also be present as isolatedanomalies in an otherwise normal individual.

The following conditions present with overlapping features:

Smith-Lemli-Opitz syndrome - (polydactyly and cleft palate are common findings).

Oculo-auriculo vertebral (Goldenhar) syndrome (OAVS) - (ear anomalies, heart disease, vertebral defects,and renalanomalies are present). OAVS often demonstrates a sporadic presentation.

Alagille syndrome - (butterfly vertebrae,congenital heart disease, and posterior embryotoxon arecommon to both conditions).

VATER association (heart disease, vertebral, renal, and limb anomalies present in both conditions). VATER association is a diagnosis of exclusion for which an established etiology to date remains unknown.

CHARGE syndrome - (any combination ofcongenital heart disease, palatal differences, atresia choanae, coloboma, renal, growth deficiency, ear anomalies/hearing loss, facial palsy, developmental differences,genitourinary anomalies, and immunodeficiency are present in both syndromes).

Genetic consult is essential along with the complete clinical picture to make an accurate diagnosis of DiGeorge syndrome.

Less than 1% of patients with 22q11.2 microdeletion have complete DGS, the most severe subtype of DGS with a very poor prognosis. Without thymic or hematopoietic cell transplantation, these patients die by 12 months of age. Even with a transplant, however, prognosis remains poor. In a study of 50 infants who received a thymic transplant for complete DGS, only 36 survived to two years.[20]

Patients with partial DGS do not have a defined prognosis, as this depends on the severity of the pathologies associated with the disease. While some do not survive infancy due to severe cardiac anomalies, many survive into adulthood. DGS may be vastly underdiagnosed, and many undiagnosed adults with DGS thrive in the community with undetectable congenital anomalies and minor intellectual and/or social impairment. Improvements in genetic diagnostics will hopefully improve understanding of DGS in the future.

Cardiac and craniofacial anomalies associated with DGS may require surgical repair. As with any surgical procedure, the possibility of complications, including bleeding, infection, and prolonged hospitalization, exists. These risks are particularly dangerous for DGS patients with significant immunocompromise.

Consistent follow-up of patients with DGS is necessary to evaluate for possiblecomplications: severe recurrent infections, autoimmune diseases, and hematologic malignancies.

Parents of children with DGS should receive patient education as it pertains to the severity of their child's condition. Discussion topics may include the following:

Early signs and symptoms of infection

Signs of hypocalcemia

Safe use of medications

Surgical intervention options

Immune therapy options

Genetic counseling

Speech therapy for feeding or language difficulty

Developmental milestones and warning signs of developmental delay

Benefits of early intervention programs

Signs and symptoms of psychiatric disorders

DiGeorge syndrome is easy to remember using the "CATCH-22" mnemonic:

Conotruncal cardiac anomalies

Abnormal facies

Thymic hypoplasia

Cleft palate

Hypocalcemia

22q11.2 microdeletion

Management of DGS requires an interprofessional approach by a team of healthcare professionals. Obstetricians and genetic counselors can assist in diagnosis and management prenatally. Neonatologists, primary care pediatricians, family medicine physicians, immunologists, cardiothoracic surgeons, pediatricians, craniofacial surgeons, and othermedical specialties may be involved in the care of patients with DGS. Collaboration with nurses, pharmacists, psychologists, speech therapists, and other healthcare professionals is paramount. Pharmacists can verify agent selection and dosing with medications to address the endocrine aspects of the disease. Nursing can counsel parents and monitor treatment progress. Psychological professionals can assist with developmental difficulties, as well as work with family members. Patients with DGS require lifelong, consistent follow-up. Because numerous organs are involved, close follow up with each specialist is necessary. Open communication and collaboration between all members of the interprofessional healthcare team are vital to ensure good outcomes. [Level 5]

Diagnosis and management can be challenging, and the interprofessional team can provide a collaborative effort to reduce morbidity and mortality associated with DGS. Current evidence regarding the management of DGS reflects level 5 evidence, and treatment options require a tailored approach around the individual patient's disease manifestations.

DiGeorge syndrome. Contributed by Professor Victor Grech (CC By=S.A. 3.0 https://creativecommons.org/licenses/by-sa/3.0/) Image courtesy: https://en.wikipedia.org/wiki/DiGeorge_syndrome#/media/File:DiGeorge_syndrome1.jpg

DiGeorge syndrome karyotype. Image courtesy O Chaigasame

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DiGeorge Syndrome - StatPearls - NCBI Bookshelf

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13.2.1 Induced pluripotent stem cells

Induced pluripotent stem cells are differentiated cells that have been reprogrammed into an embryonic stem cell like state by the ectopic overexpression of four stem cell specific transcription factors, Oct3/4, Klf4, Sox2, and c-Myc, collectively referred to as OKSM. Induced pluripotent stem cells were first derived in a groundbreaking experiment by Yamanaka and Takashi in 2006 [77]. The team assessed the ability of 24 pluripotency associated candidate genes to covert primarily differentiated mouse tail tip fibroblasts into an embryonic stem cell state. Candidate genes were packaged into individual retroviruses and transduced into Fbx15geo/geo cells, which were grown in G418 containing media, an aminoglycoside antibiotic with conferred resistance to the neomycin gene. If the cells converted to an ESC like fate the embryonic stem cell specific locus Fbx15 containing a -galactosidase and neomycin fused reporter cassette would become activated, thereby inoculating the cells against neomycin. Transduction with all 24 factors proved to be successful in converting the fibroblasts into ESCs. Through the process of elimination, the team narrowed the list of factors down to just four factors needed to reprogram fibroblast cells to an ESC state [77]. Yamanaka and Takashi expanded their groundbreaking discovery to human cells a year later [78].

The discovery of induced pluripotent stem cells ignited the field with possibility. It was a new research tool that could be used to analyze development and cell specialization. Additionally, the possibility of deriving pluripotent stem cells was also a new therapeutic research tool that if harnessed and understood could be used for personalized cell therapy and disease modeling. Researchers quickly began differentiating iPSCs into different cell lineages.

Induced pluripotent stem cell derived-cardiomyocytes (iPSC-CMs) were generated similarly to established methods for differentiating embryonic stem cells into cardiomyocytes [7981] (Fig.13.1C). The cells were first differentiated into embryoid bodies and then exposed to serum-containing medium, which fostered a propensity to differentiate into cardiomyocytes. After 50 or more days in culture, cells derived under these conditions stained positive for sarcomeric myosin light and heavy chains, cardiac troponin T, and alpha-actinin. Additionally, the embryoid bodies demonstrated action potentials akin to atrial, ventricular, and nodal cells, and underwent rapid adaptive response to electrical stimulation and were cable of visible contractions. Despite well-established protocols the purity of cardiomyocytes derived using this technique are often times lower than 1% [8284]. However, the efficiency and purity of cardiomyocytes generated from embryoid body differentiation could be enhanced by following a step wise induction process similar to the naturally occurring cardiac differentiation process in the developing embryo [85].

To increase purity, and the usability for downstream applications monolayer culture methods were developed to facilitate a more controllable and reproducible environment to generate iPSC-CMs [86]. Monoculture conditions consist of growth on Matrigel-coated plates with mouse embryonic fibroblast conditioned media and gradual supplementation with activin A and BMP-4 growth factors. The combination of these conditions have been shown to yield greater than 50% beating iPSC-CMs [87,88]. A variation of this method, called the matrix sandwich method exists and boasts yields of up to 98% beating iPSC-CMs [89]. However, it should be noted that this method only works for some cell lines and requires growth factor batch optimizations to maintain high yields [90]. Alternatively, modifying Wnt/-catenin signaling using shRNA and small molecules has also been shown to increase iPSC-CM yield to approximately 85% [91,92].

The need for complex culture conditions to yield high iPSC-CM outputs makes identifying the biological underpinnings of iPSC-CM differentiation difficult to elucidate. One study claims to have reduced the complexity of iPSC-CM derivation to just three components, referred to as CDM3 [93]. When used in combination with lactate selection the study authors claim to achieve a yield of 80%90% troponin T positive iPSC-CMs [94]. The simplicity of the culture conditions used in this study allowed for the first time the identification of key signaling pathways implicated in iPSC-CM carcinogenesis.

The first and only case thus far of an autologous iPSC derived cell treatment making it to the clinic was reported in 2014. In a trial lead by Takahashi and colleagues, human iPSC derived retinal pigment epithelium cell sheets were transplanted into a human patient to resolve age related macular regeneration [95]. There have been no clinical trials testing iPSC-CM safety or efficacy in repairing the injured heart. However, iPSC-CMs derived using the previously mentioned matrix sandwich technique were transplanted in a non-human primate model, where they were shown to improve cardiac function after induced myocardial infraction. However, the transplanted iPSC-CMs also induced high rates of ventricular arrhythmia [96].

Despite the great hope for patient specific treatments, it is uncertain if autologous iPSC-CM treatments for myocardial infractions will make it to the clinic within the next few years. The production of patient-specific stem cells is expensive and variable. Specifically, iPSC-CM derivation efficiency still remains low and variable without the use of complex culture systems. Streamlining human iPSC cardiomyocyte differentiation to an effective simple differentiation process is key. Large numbers of iPSC-CM cells would be needed for human clinical trials, which would be impractical to accomplish using current culture systems and methods. Currently macaque trials require about 108109 reprogrammed iPSC-CM cells. The number of cells required for a human trial is projected to be a least a magnitude higher [5,97]. Additionally, like all iPSC derived cell therapies, and even embryonic stem cell therapies there is the concern that the transplanted stem cells could develop into tumor and/or cancer cells because of the possible carryover of few highly multi- or pluripotent cells in the transplanted pool [98]. Safety assessment is key before any iPSC-CM trial can make it to the clinical setting.

However, iPSC-CMs do have the potential to be somewhat useful for in vitro screening assays and drug development. iPSC-CMs have been used to improve the identification of false positive and negative data in electrophysiological assays [99]. They have also been shown to be responsive for research purposes to several cardiac and non-cardiac drugs, a prospect that might be of interest for drug screening purposes [100103]. Furthermore, disease-specific iPSC-CMs derived from people with pre-existing heart conditions have been shown to be more responsive to cardiotoxic drugs as measured by action potential duration and drug-induced arrhythmia, consistent with what would be expected naturally in the patient [104].

While iPSC-CMs might have some usefulness for drug screening, the results should be considered in light of the fact that iPSC-CMs are not equivalent to true CMs found in the adult heart. iPSC-CMs have lower conduction velocities and shorter action potential duration. They are altogether functionally immature, disorganized, fetal-like, and are not molecularly equivalent to true cardiomyocytes found in the adult heart [90,105107]. There is a need to understand cardiomyocyte maturation to facilitate regeneration and differentiation into cardiomyocytes capable of maintaining the functions of an adult heart.

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Induced Pluripotent Stem Cell - an overview - ScienceDirect

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Stem Cells Definition

Stem cells are unique cells present in the body that have the potential to differentiate into various cell types or divide indefinitely to produce other stem cells.

Figure: Stem Cell Renewal and Differentiation. Image Source: Maharaj Institute of Immune Regenerative Medicine.

All the stem cells found throughout all living systems have three important properties. These properties can be visualized in vitro by a process called clonogenic assays, where a single cell is assessed for its ability to differentiate.

The following are some properties of stem cells:

Figure: Techniques for generating embryonic stem cell cultures. Image Source: John Wiley & Sons, Inc. (Nico Heins et al.)

Depending on the source of the stem cells or where they are present, stem cells are divided into various types;

Figure: Human Embryonic Stem Cells Differentiation. Image created with biorender.com

Figure: Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells. Image Source: NIH Stem Cell Information.

Figure: Progress in therapies based on iPSCs. Image Source: Nature Reviews Genetics (R. Grant Rowe & George Q. Daley).

Figure: Mesenchymal stem cells (MSCs). Image Source: PromoCell GmbH.

Some of the common and well-known examples of stem cell research are:

Stem cell research has been used in various areas because of their properties. Some of the common applications of stem cells research include;

Because of different ethical and other issues related to stem cell research, there are some limitations or challenges of stem cell research. Some of these are:

Read Also:

Read more here:
Stem Cells- Definition, Properties, Types, Uses, Challenges - Microbe Notes

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Your body controls your thyroid hormone (T3 and T4) levels through a complex feedback loop. Your hypothalamus releases thyrotropin-releasing hormone (TRH), which triggers your pituitary gland to release thyroid-stimulating hormone (TSH), which stimulates your thyroid to release T3 and T4.What is thyroid hormone?

Thyroid hormone is the hormone thats mainly responsible for controlling the speed of your bodys metabolism. In infants, thyroid hormone is critical for brain development. Your thyroid, a small, butterfly-shaped gland located at the front of your neck under your skin, makes and releases thyroid hormone. Its a part of your endocrine system.

Hormones are chemicals that coordinate different functions in your body by carrying messages through your blood to your organs, muscles and other tissues. These signals tell your body what to do and when to do it.

Metabolism is the complex process of how your body transforms the food you consume into energy. All of the cells in your body need energy to function.

Thyroid hormone actually represents the combination of the two main hormones that your thyroid gland releases: thyroxine (T4) and triiodothyronine (T3). Theyre often collectively referred to as thyroid hormone because T4 is largely inactive, meaning it doesnt impact your cells, whereas T3 is active. Once your thyroid releases T4, certain organs in your body transform it into T3 so that it can impact your cells and your metabolism.

Your thyroid also releases a hormone called calcitonin to help regulate calcium levels in your blood by decreasing it. Calcitonin isnt grouped into the thyroid hormone name, and it doesnt impact your bodys metabolism like T3 and T4 do.

The production and release of thyroid hormone thyroxine (t4) and triiodothyronine (T3) is controlled by a feedback loop system that involves the following:

Your hypothalamus is the part of your brain that controls functions like blood pressure, heart rate, body temperature and digestion.

Your pituitary gland is a small, pea-sized gland located at the base of your brain below your hypothalamus. It makes and releases eight hormones.

Your pituitary gland is connected to your hypothalamus through a stalk of blood vessels and nerves. This is called the pituitary stalk. Through the stalk, your hypothalamus communicates with your pituitary gland and tells it to release certain hormones.

To start the feedback loop, your hypothalamus releases thyroid-releasing hormone (TRH) which, in turn, stimulates your pituitary gland to produce and release thyroid-stimulating hormone (TSH). TSH then triggers your thyroid to produce T4 and T3. Of the total amount of hormones that TSH triggers your thyroid to release, about 80% is T4 and 20% is T3. Your thyroid also needs adequate amounts of iodine, a substance you get from the food you eat, to create T4 and T3.

This hormone chain reaction is regulated by a feedback loop so that when the levels of T3 and T4 increase, they prevent the release of TRH (and thus TSH). When T3 and T4 levels drop, the feedback loop starts again. This system allows your body to maintain a constant level of thyroid hormones in your body.

If there are any issues with your hypothalamus, pituitary gland or thyroid, it can result in an imbalance in the hormones involved in this system, including T3 and T4.

Once your thyroid releases thyroxine (T4) into your bloodstream, certain cells in your body transform it into triiodothyronine (T3) through a process called de-iodination. This is because cells that have receptors that receive the effect of thyroid hormone are better able to use T3 than T4. Therefore, T4 is generally considered to be the inactive form of thyroid hormone, and T3 is considered the active form of it.

Cells in the following tissues, glands, organs and body systems can convert T4 to T3:

Thyroid hormone (T3 and T4) affects every cell and all the organs in your body by:

Several blood tests can measure your thyroid levels and assess how well your thyroid is working. These tests are often called thyroid function tests and include:

Your provider may order additional tests to assess your thyroid function, including:

Several conditions can result from or cause abnormal thyroid hormone levels. Thyroid disease is very common, with an estimated 20 million people in the United States having some type of thyroid condition. A person assigned female at birth is about five to eight times more likely to have a thyroid condition than a person assigned male at birth.

Thyroid conditions include:

Issues with your pituitary gland or hypothalamus can also cause abnormal thyroid hormone levels since they help control thyroid hormone levels.

Abnormal thyroid hormone levels usually cause noticeable symptoms. Since thyroid hormone is responsible for controlling the speed of your metabolism, too much thyroid hormone can make it faster than normal and too little thyroid hormone can slow it down. These imbalances cause certain symptoms, including:

If you experience these symptoms, contact your healthcare provider. They can run some simple blood tests to see if your thyroid hormone levels are irregular.

A note from Cleveland Clinic

Thyroid hormone is an essential hormone that affects many aspects of your body. Sometimes, you can have too little or too much thyroid hormone. The good news is that thyroid conditions are highly treatable. If youre experiencing any thyroid hormone-related symptoms or want to know if you have any risk factors for developing thyroid disease, dont be afraid to talk to your healthcare provider. Theyre there to help you.

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Thyroid Hormone: What It Is & Function - Cleveland Clinic

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What is human chorionic gonadotrophin?

Human chorionic gonadotrophin (hCG) is a hormone produced by the placenta during pregnancy. Its sometimes called the pregnancy hormone because of its unique role in supporting a pregnancy. HCG is found in your urine or blood around 10 to 11 days after conception (when a sperm fertilizes an egg). Your hCG levels are the highest towards the end of the first trimester (10 weeks of pregnancy), then decline for the rest of your pregnancy. Healthcare providers measure hCG to confirm a pregnancy and provide details on how the pregnancy is progressing.

After conception occurs, a fertilized egg travels through your fallopian tubes to your uterus. The fertilized egg (called an embryo) implants (attaches) into the wall of your uterus. This triggers the placenta to form. Your placenta begins producing and releasing hCG into your blood and urine. HCG can be found in a persons blood around 11 days after conception. It takes slightly longer for hCG to register on urine tests.

HCG increases quickly (almost doubling every three days) for the first eight to 10 weeks of pregnancy. Healthcare providers look at how quickly a persons hCG levels rise in early pregnancy to determine how the pregnancy and fetus are developing.

Once your placenta begins making hCG, it triggers your body to create more estrogen and progesterone. Together with hCG, these hormones help thicken your uterine lining and tell your body to stop menstruating (or releasing eggs). The correct balance of these three hormones sustains and supports the pregnancy.

This chart shows how your hCG levels rise quickly and steadily in the first trimester before declining:

These numbers should be used as a guide only. Your levels may rise differently. Its not the number that matters as much as how the number changes. Your healthcare provider will let you know if your hCG levels need to be checked and what your test results mean for your pregnancy. Remember that healthy pregnancies may have lower than average hCG levels.

HCG can be detected in either blood or urine. However, a blood test is more accurate because it can detect smaller amounts of hCG.

There are two different types of blood tests to detect hCG:

An at-home pregnancy test will be positive if hCG is detected in your urine. A urine hCG test is performed by either peeing on a chemical strip or placing a drop of urine on a chemical strip. At-home urine tests typically require higher hCG levels to return a positive.

Keep in mind a low hCG level doesnt diagnose anything. Its a tool to detect potential issues. If your healthcare provider is concerned about your hCG level, they will test your levels again in two or three days. Then, they will compare the results to get a better picture of whats going on with your pregnancy.

HCG levels are typically not checked more than once or twice during pregnancy. Healthcare providers check hCG levels in the first trimester but usually dont need to check again. If initial hCG levels are lower than average, your provider will test hCG levels again in a few days. Assessing hCG levels is done sequentially, testing several days apart and comparing levels. Some prenatal genetic tests use hCG levels to check for the possibility of a fetus having a congenital disorder.

All people have small amounts of hCG in their bodies (almost undetectable levels). Your hCG levels rise fast and peak around 10 weeks of pregnancy. After that, they fall gradually until childbirth. In rare cases, germ cell tumors or other cancers may cause your body to produce hCG.

A low or declining hCG level may mean several things:

If your hCG level is low for the gestational age of the pregnancy, your healthcare provider will recheck your hCG levels in two or three days or perform an ultrasound to get a better look at your uterus.

High levels of hCG could indicate:

HCG injections can increase your chances of becoming pregnant when used with IVF (in-vitro fertilization) or IUI (intrauterine insemination). It works by inducing ovulation (when ovaries release an egg).

If you have a history of infertility, monitoring hCG levels early in pregnancy can help healthcare providers determine if a successful pregnancy has occurred.

HCG helps with the production of testosterone and sperm in people assigned male at birth (AMAB). Its also been used to treat undescended testicles in male infants.

Most of the time, youre unaware of your hCG levels other than when you take an at-home pregnancy test. Your healthcare provider may tell you your hCG levels are low based on the gestational age of the pregnancy. Obstetricians typically check hCG early on in pregnancy but dont continue to check it unless there are signs of problems. If your healthcare provider is concerned about how your pregnancy is progressing, they will recheck hCG levels and perform other diagnostic tests like ultrasound.

A note from Cleveland Clinic

Human chorionic gonadotropin (hCG) is known as the pregnancy hormone. Its claim to fame is that its the hormone at-home pregnancy tests check for. Your body produces a lot of hCG during the first trimester to support your growing baby. Your hCG levels provide valuable insight into your pregnancy and may alert your obstetrician to potential issues. However, if your pregnancy is going well, chances are you wont ever know what your hCG levels are. Contact your healthcare provider if you have questions about your hCG levels or what they mean.

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Human Chorionic Gonadotropin: Hormone, Purpose & Levels - Cleveland Clinic

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Overview

Menopause is the time that marks the end of your menstrual cycles. It's diagnosed after you've gone 12 months without a menstrual period. Menopause can happen in your 40s or 50s, but the average age is 51 in the United States.

Menopause is a natural biological process. But the physical symptoms, such as hot flashes, and emotional symptoms of menopause may disrupt your sleep, lower your energy or affect emotional health. There are many effective treatments available, from lifestyle adjustments to hormone therapy.

In the months or years leading up to menopause (perimenopause), you might experience these signs and symptoms:

Signs and symptoms, including changes in menstruation can vary among women. Most likely, you'll experience some irregularity in your periods before they end.

Skipping periods during perimenopause is common and expected. Often, menstrual periods will skip a month and return, or skip several months and then start monthly cycles again for a few months. Periods also tend to happen on shorter cycles, so they are closer together. Despite irregular periods, pregnancy is possible. If you've skipped a period but aren't sure you've started the menopausal transition, consider a pregnancy test.

Keep up with regular visits with your doctor for preventive health care and any medical concerns. Continue getting these appointments during and after menopause.

Preventive health care as you age may include recommended health screening tests, such as colonoscopy, mammography and triglyceride screening. Your doctor might recommend other tests and exams, too, including thyroid testing if suggested by your history, and breast and pelvic exams.

Always seek medical advice if you have bleeding from your vagina after menopause.

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Menopause can result from:

Naturally declining reproductive hormones. As you approach your late 30s, your ovaries start making less estrogen and progesterone the hormones that regulate menstruation and your fertility declines.

In your 40s, your menstrual periods may become longer or shorter, heavier or lighter, and more or less frequent, until eventually on average, by age 51 your ovaries stop releasing eggs, and you have no more periods.

Surgery that removes the ovaries (oophorectomy). Your ovaries produce hormones, including estrogen and progesterone, that regulate the menstrual cycle. Surgery to remove your ovaries causes immediate menopause. Your periods stop, and you're likely to have hot flashes and experience other menopausal signs and symptoms. Signs and symptoms can be severe, as hormonal changes occur abruptly rather than gradually over several years.

Surgery that removes your uterus but not your ovaries (hysterectomy) usually doesn't cause immediate menopause. Although you no longer have periods, your ovaries still release eggs and produce estrogen and progesterone.

After menopause, your risk of certain medical conditions increases. Examples include:

Urinary incontinence. As the tissues of your vagina and urethra lose elasticity, you may experience frequent, sudden, strong urges to urinate, followed by an involuntary loss of urine (urge incontinence), or the loss of urine with coughing, laughing or lifting (stress incontinence). You may have urinary tract infections more often.

Strengthening pelvic floor muscles with Kegel exercises and using a topical vaginal estrogen may help relieve symptoms of incontinence. Hormone therapy may also be an effective treatment option for menopausal urinary tract and vaginal changes that can result in urinary incontinence.

Sexual function. Vaginal dryness from decreased moisture production and loss of elasticity can cause discomfort and slight bleeding during sexual intercourse. Also, decreased sensation may reduce your desire for sexual activity (libido).

Water-based vaginal moisturizers and lubricants may help. If a vaginal lubricant isn't enough, many women benefit from the use of local vaginal estrogen treatment, available as a vaginal cream, tablet or ring.

Dec. 17, 2022

See more here:
Menopause - Symptoms and causes - Mayo Clinic

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Overview Polycystic ovary syndrome Open pop-up dialog box

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Polycystic ovary syndrome is a condition where you have few, unusual or very long periods. It often results in having too much of a male hormone called androgen. Many small sacs of fluid develop on the ovaries. They may fail to regularly release eggs.

Polycystic ovary syndrome (PCOS) is a problem with hormones that happens during the reproductive years. If you have PCOS, you may not have periods very often. Or you may have periods that last many days. You may also have too much of a hormone called androgen in your body.

With PCOS, many small sacs of fluid develop along the outer edge of the ovary. These are called cysts. The small fluid-filled cysts contain immature eggs. These are called follicles. The follicles fail to regularly release eggs.

The exact cause of PCOS is unknown. Early diagnosis and treatment along with weight loss may lower the risk of long-term complications such as type 2 diabetes and heart disease.

Symptoms of PCOS often start around the time of the first menstrual period. Sometimes symptoms develop later after you have had periods for a while.

The symptoms of PCOS vary. A diagnosis of PCOS is made when you have at least two of these:

PCOS signs and symptoms are typically more severe in people with obesity.

See your health care provider if you're worried about your periods, if you're having trouble getting pregnant, or if you have signs of excess androgen. These might include new hair growth on your face and body, acne and male-pattern baldness.

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The exact cause of PCOS isn't known. Factors that might play a role include:

Insulin resistance. Insulin is a hormone that the pancreas makes. It allows cells to use sugar, your body's primary energy supply. If cells become resistant to the action of insulin, then blood sugar levels can go up. This can cause your body to make more insulin to try to bring down the blood sugar level.

Too much insulin might cause your body to make too much of the male hormone androgen. You could have trouble with ovulation, the process where eggs are released from the ovary.

One sign of insulin resistance is dark, velvety patches of skin on the lower part of the neck, armpits, groin or under the breasts. A bigger appetite and weight gain may be other signs.

Complications of PCOS can include:

Obesity commonly occurs with PCOS and can worsen complications of the disorder.

Polycystic ovary syndrome (PCOS) care at Mayo Clinic

Sept. 08, 2022

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Polycystic ovary syndrome (PCOS) - Symptoms and causes - Mayo Clinic

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OverviewWhat is hypothyroidism?

Hypothyroidism is a condition where there isnt enough thyroid hormone in your bloodstream and your metabolism slows down.

Hypothyroidism happens when your thyroid doesnt create and release enough thyroid hormone into your body. This makes your metabolism slow down, affecting you entire body. Also known as underactive thyroid disease, hypothyroidism is fairly common.

When your thyroid levels are extremely low, this is called myxedema. A very serious condition, myxedema can cause serious symptoms, including:

This severe type of hypothyroidism is life-threatening.

In general, hypothyroidism is a very treatable condition. It can be managed with regular medications and follow-up appointments with your healthcare provider.

The thyroid gland is a small, butterfly-shaped organ located in the front of your neck just under the voice box (larynx). Picture the middle of the butterflys body centered on your neck, with the wings hugging around your windpipe (trachea). The main job of the thyroid is to control your metabolism. Metabolism is the process that your body uses to transform food to energy your body uses to function. The thyroid creates the hormones T4 and T3 to control your metabolism. These hormones work throughout the body to tell the bodys cells how much energy to use. They control your body temperature and heart rate.

When your thyroid works correctly, its constantly making hormones, releasing them and then making new hormones to replace whats been used. This keeps your metabolism functioning and all of your bodys systems in check. The amount of thyroid hormones in the bloodstream is controlled by the pituitary gland, which is located in the center of the skull below the brain. When the pituitary gland senses either a lack of thyroid hormone or too much, it adjusts its own hormone (thyroid stimulating hormone, or TSH) and sends it to the thyroid to balance out the amounts.

If the amount of thyroid hormones is too high (hyperthyroidism) or too low (hypothyroidism), the entire body is impacted.

Hypothyroidism can affect people of all ages, genders and ethnicities. Its a common condition, particularly among women over age 60. Women are generally more likely to develop hypothyroidism after menopause than earlier in life.

In hypothyroidism, the thyroid doesnt make enough thyroid hormone.

The difference between hypothyroidism and hyperthyroidism is quantity. In hypothyroidism, the thyroid makes very little thyroid hormone. On the flip side, someone with hyperthyroidism has a thyroid that makes too much thyroid hormone. Hyperthyroidism involves higher levels of thyroid hormones, which makes your metabolism speed up. If you have hypothyroidism, your metabolism slows down.

Many things are the opposite between these two conditions. If you have hypothyroidism, you may have a difficult time dealing with the cold. If you have hyperthyroidism, you may not handle the heat. They are opposite extremes of thyroid function. Ideally, you should be in the middle. Treatments for both of these conditions work to get your thyroid function as close to that middle ground as possible.

Hypothyroidism can have a primary cause or a secondary cause. A primary cause is a condition that directly impacts the thyroid and causes it to create low levels of thyroid hormones. A secondary cause is something that causes the pituitary gland to fail, which means it cant send thyroid stimulating hormone (TSH) to the thyroid to balance out the thyroid hormones.

Primary causes of hypothyroidism are much more common. The most common of these primary causes is an autoimmune condition called Hashimotos disease. Also called Hashimotos thyroiditis or chronic lymphocytic thyroiditis, this condition is hereditary (passed down through a family). In Hashimotos disease, the bodys immune system attacks and damages the thyroid. This prevents the thyroid from making and releasing enough thyroid hormone.

The other primary causes of hypothyroidism can include:

In some cases, thyroiditis can happen after a pregnancy (postpartum thyroiditis) or a viral illness.

In most cases, women with hypothyroidism during pregnancy have Hashimotos disease. This autoimmune disease causes the bodys immune system to attack and damage the thyroid. When that happens, the thyroid cant produce and release high enough levels of thyroid hormones, impacting the entire body. Pregnant people with hypothyroidism may feel very tired, have a hard time dealing with cold temperatures and experience muscles cramps.

Thyroid hormones are important to fetal development. These hormones help develop the brain and nervous system. If you have hypothyroidism, its important to manage your thyroid levels during pregnancy. If the fetus doesnt get enough thyroid hormone during development, the brain may not develop correctly and there could be issues later. Untreated or insufficiently treated hypothyroidism during pregnancy may lead to complications like miscarriage or preterm labor.

When youre on birth control pills, the estrogen and progesterone inside of the pills can affect your thyroid-binding proteins. This increases your levels. If you have hypothyroidism, the dose of your medications will need to be increased while youre using birth control pills. Once you stop using birth control pills, the dosage will need to be lowered.

In some cases, there can be a connection between untreated hypothyroidism and erectile dysfunction. When your hypothyroidism is caused by an issue with the pituitary gland, you can also have low testosterone levels. Treating hypothyroidism can often help with erectile dysfunction if it was directly caused by the hormone imbalance.

The symptoms of hypothyroidism usually develop slowly over time sometimes years. They can include:

If your hypothyroidism is not treated, you could gain weight. Once you are treating the condition, the weight should start to lower. However, you will still need to watch your calories and exercise to lose weight. Talk to your healthcare provider about weight loss and ways to develop a diet that works for you.

It can actually be difficult to diagnose hypothyroidism because the symptoms can be easily confused with other conditions. If you have any of the symptoms of hypothyroidism, talk to your healthcare provider. The main way to diagnose hypothyroidism is a blood test called the thyroid stimulating hormone (TSH) test. Your healthcare provider may also order blood tests for conditions like Hashimotos disease. If the thyroid is enlarged, your provider may be able to feel it during a physical exam during an appointment.

In most cases, hypothyroidism is treated by replacing the amount of hormone that your thyroid is no longer making. This is typically done with a medication. One medication that is commonly used is called levothyroxine. Taken orally, this medication increases the amount of thyroid hormone your body produces, evening out your levels.

Hypothyroidism is a manageable disease. However, you will need to continuously take medication to normalize the amount of hormones in your body for the rest of your life. With careful management, and follow-up appointments with your healthcare provider to make sure your treatment is working properly, you can lead a normal and healthy life.

Hypothyroidism can become a serious and life-threatening medical condition if you do not get treatment from a healthcare provider. If you are not treated, your symptoms can become more severe and can include:

You can also develop a serious medical condition called myxedema coma. This can happen when hypothyroidism isnt treated.

The dose of your medication can actually change over time. At different points in your life, you may need to have the amounts of medication changed so that it manages your symptoms. This could happen because of things like weight gain or weight loss. Your levels will need to be monitored throughout your life to make sure your medication is working correctly.

Hypothyroidism cannot be prevented. The best way to prevent developing a serious form of the condition or having the symptoms impact your life in a serious way is to watch for signs of hypothyroidism. If you experience any of the symptoms of hypothyroidism, the best thing to do is talk to your healthcare provider. Hypothyroidism is very manageable if you catch it early and begin treatment.

Most foods in western diets contain iodine, so you do not have to worry about your diet. Iodine is a mineral that helps your thyroid produce hormones. One idea is that if you have low levels of thyroid hormone, eating foods rich in iodine could help increase your hormone levels. The most reliable way to increase your hormone levels is with a prescription medication from your healthcare provider. Do not try any new diets without talking to your provider first. Its important to always have a conversation before starting a new diet, especially if you have a medical condition like hypothyroidism.

Foods that are high in iodine include:

Work with your healthcare provider or a nutritionist (a healthcare provider who specializes in food) to craft a meal plan. Your food is your fuel. Making sure you are eating foods that will help your body, along with taking your medications as instructed by your healthcare provider, can keep you healthy over time. People with thyroid condition should not consume large amounts of iodine because the effect may be paradoxical (self-contradictory).

In some mild cases, you may not have symptoms of hypothyroidism or the symptoms may fade over time. In other cases, the symptoms of hypothyroidism will go away shortly after you start treatment. For those with particularly low levels of thyroid hormones, hypothyroidism is a life-long condition that will need to be managed with medication on a regular schedule.

Read this article:
Hypothyroidism: Symptoms, Causes, Treatment & Medication - Cleveland Clinic

Recommendation and review posted by Bethany Smith

Overview

The birth of a baby can start a variety of powerful emotions, from excitement and joy to fear and anxiety. But it can also result in something you might not expect depression.

Most new moms experience postpartum "baby blues" after childbirth, which commonly include mood swings, crying spells, anxiety and difficulty sleeping. Baby blues usually begin within the first 2 to 3 days after delivery and may last for up to two weeks.

But some new moms experience a more severe, long-lasting form of depression known as postpartum depression. Sometimes it's called peripartum depression because it can start during pregnancy and continue after childbirth. Rarely, an extreme mood disorder called postpartum psychosis also may develop after childbirth.

Postpartum depression is not a character flaw or a weakness. Sometimes it's simply a complication of giving birth. If you have postpartum depression, prompt treatment can help you manage your symptoms and help you bond with your baby.

Symptoms of depression after childbirth vary, and they can range from mild to severe.

Symptoms of baby blues which last only a few days to a week or two after your baby is born may include:

Postpartum depression may be mistaken for baby blues at first but the symptoms are more intense and last longer. These may eventually interfere with your ability to care for your baby and handle other daily tasks. Symptoms usually develop within the first few weeks after giving birth. But they may begin earlier during pregnancy or later up to a year after birth.

Postpartum depression symptoms may include:

Untreated, postpartum depression may last for many months or longer.

With postpartum psychosis a rare condition that usually develops within the first week after delivery the symptoms are severe. Symptoms may include:

Postpartum psychosis may lead to life-threatening thoughts or behaviors and requires immediate treatment.

Studies show that new fathers can experience postpartum depression, too. They may feel sad, tired, overwhelmed, anxious, or have changes in their usual eating and sleeping patterns. These are the same symptoms that mothers with postpartum depression experience.

Fathers who are young, have a history of depression, experience relationship problems or are struggling financially are most at risk of postpartum depression. Postpartum depression in fathers sometimes called paternal postpartum depression can have the same negative effect on partner relationships and child development as postpartum depression in mothers can.

If you're a partner of a new mother and are having symptoms of depression or anxiety during your partner's pregnancy or after your child's birth, talk to your health care provider. Similar treatments and supports provided to mothers with postpartum depression can help treat postpartum depression in the other parent.

If you're feeling depressed after your baby's birth, you may be reluctant or embarrassed to admit it. But if you experience any symptoms of postpartum baby blues or postpartum depression, call your primary health care provider or your obstetrician or gynecologist and schedule an appointment. If you have symptoms that suggest you may have postpartum psychosis, get help immediately.

It's important to call your provider as soon as possible if the symptoms of depression have any of these features:

If at any point you have thoughts of harming yourself or your baby, immediately seek help from your partner or loved ones in taking care of your baby. Call 911 or your local emergency assistance number to get help.

Also consider these options if you're having suicidal thoughts:

People with depression may not recognize or admit that they're depressed. They may not be aware of signs and symptoms of depression. If you suspect that a friend or loved one has postpartum depression or is developing postpartum psychosis, help them seek medical attention immediately. Don't wait and hope for improvement.

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There is no single cause of postpartum depression, but genetics, physical changes and emotional issues may play a role.

Any new mom can experience postpartum depression and it can develop after the birth of any child, not just the first. However, your risk increases if:

Left untreated, postpartum depression can interfere with mother-child bonding and cause family problems.

If you have a history of depression especially postpartum depression tell your health care provider if you're planning on becoming pregnant or as soon as you find out you're pregnant.

Nov. 24, 2022

View post:
Postpartum depression - Symptoms and causes - Mayo Clinic

Recommendation and review posted by Bethany Smith

Let's Talk Sex | Unpacking the Mystery of PCOS: Causes, Symptoms and Treatments  News18

Original post:
Let's Talk Sex | Unpacking the Mystery of PCOS: Causes, Symptoms and Treatments - News18

Recommendation and review posted by Bethany Smith

Stem Cell Therapy

Cell therapy involves the direct administration of cells into the body for healing purposes. The units of therapy in this approach are single cells. For regenerative medicine, the ultimate objective of cell therapy is to establish a long-term graft with the capacity to perform organ functions. A practical example is bone marrow transplantation, in which HSC are the units of therapy, engraft in the bone marrow, and repopulate the entire blood lineage.105

Intravenous administration describes the direct injection of dissociated cells into the bloodstream using a syringe. It is the simplest delivery route for cell therapies and is used for HSC therapy in the clinic. Kidney cells, however, are different from blood cells and do not typically circulate throughout the body. The kidney is furthermore a densely-packed organ with no obvious route for stem cells to traverse from the bloodstream into the nephrons. Whether kidney stem cells have the ability to engraft and regenerate the kidney after intravenous administration therefore needs to be tested in preclinical animal models. In these experiments, the kidneys are typically subjected to acute injury. This damages the glomerular filtration barrier, which can enhance penetration of cells into the kidney and subsequent engraftment.

In one example, human iPS cell-derived cells expressing a variety of NPC and adult kidney cell markers were injected into the mouse tail vein 24 hours after administration of the nephrotoxic drug cisplatin.106 Extensive engraftment was reported in proximal tubules, which coincided with a 55% reduction in urea levels in treated mice, compared with control animals administered with saline or undifferentiated iPS cells.106 These experiments suggest a possible benefit of iPS-derived kidney cells on kidney injury. However, the isolated cells were not shown to demonstrate the ability to form kidney organoids with segmented nephrons. It is therefore unclear whether the implanted cells contained bona fide NPC or whether new nephrons were actually formed.

Intravenous administration has also been applied to adult kidney cell populations. Human glomerular epithelial transitional cells (see earlier), administered intravenously into a mouse model of chemically-induced podocytopathy, were found in glomeruli, and were associated with a decrease in proteinuria.107 These cells also contributed to tubules after acute injury.80 As these cells cannot form new nephrons, this approach seeks to repair and replace, rather than to completely regenerate.

MSC can be readily obtained, for instance from a patient's adipose tissue. Intravenous administration of MSC in experimental models can have a beneficial effect on ischemia-reperfusion injury.99,102,108 This benefit can be obtained even in the absence of MSC engraftment, likely via a paracrine effect. However, MSC administered to injured kidneys do not contribute tangibly to new nephron formation and can differentiate ectopically into undesirable fat cells or fibroblasts within glomeruli.108,109 Collectively, these findings suggest that intravenous administration of cell therapeutics may provide some benefit in cases where the glomerular filtration barrier has been compromised but may also have unwanted side effects.

Originally posted here:
Cell Therapy - an overview | ScienceDirect Topics

Recommendation and review posted by Bethany Smith

Since 2017, Cell & Gene Therapy World Asia haswitnessed huge success in bringing over 300industry pioneers from both cell & gene therapyindustry. With the mission to facilitate the research& development and manufacturing of high qualitycell & gene therapy treatments and regenerativemedicines in Asia, Cell & Gene Therapy World Asia isgoing to continue its legacy.

In addition, this year, speakers will be exploringinnovations in cell & gene therapy in Asia region,best practices on cell & gene therapymanufacturing and process development, scale outstrategies, cost optimization, next generation onCART, advances in CART manufacturing,preparation for commercialization, regulation casestudies and more.

Join the conference to interact with key andupcoming entities from Asia cell & gene therapycompanies including BeiGene, GracellBiotechnologies, Fosun Kite Biotechnology, TessaTherapeutics, CARSgen, Senlang Bio, KangstemBiotech, Medigen Biotechnology Corp, ShangaiUniCAR Therapy among others.

Catch the latest cell & gene therapy development inAsia. From current best R&D practices to advancingtowards manufacturing and commercializationfrom most-exclusive case studies to industry's keyneeds. All this and more under 1 roof.

See the article here:
Cell and Gene Therapy World Asia Event - IMAPAC

Recommendation and review posted by Bethany Smith

Parkinsons disease is a neurological disorder with symptoms that become more severe over time. It affects about 1% of people ages 60 years and older in industrialized nations. The exact cause of the disease isnt known, but experts believe that both genetic and environmental factors play a role.

Parkinsons disease causes neurons to die in certain parts of your brain, leading to a decrease of dopamine. Dopamine is a neurotransmitter. Cells in your brain release dopamine as a way of sending signals to other nearby cells.

When you have Parkinsons, a decrease in dopamine activity can lead to such symptoms as:

Theres no cure for Parkinsons disease. But over the past few decades, researchers have been studying stem cell therapy to provide better treatment options.

Read on to learn more about current and future developments in using stem cell therapy to treat Parkinsons disease.

Stem cells are special because theyre undifferentiated, meaning they have the potential to become many types of specialized cells.

You might think of stem cells as natural resources for your body. When your body needs a specific type of cell from bone cells to brain cells an undifferentiated stem cell can transform to fit the need.

There are three main types of stem cells:

Stem cell therapy is the use of stem cells usually from a donor, but sometimes from your own body to treat a disorder.

Because Parkinsons disease leads to the death of brain cells, researchers are trying to use stem cells to replace brain cells in the affected areas. This could help treat the symptoms of Parkinsons disease.

Researchers are exploring various approaches to use stem cells to treat Parkinsons disease.

The current idea is to introduce stem cells directly into the affected areas of your brain where they can transform into brain cells. These new brain cells could then help regulate dopamine levels, which should improve the symptoms of the disease.

Its important to note that experts believe this would only be a treatment for Parkinsons disease and not a cure.

While stem cell therapy has the potential to replace the brain cells destroyed by Parkinsons disease, the disease would still be present. Parkinsons disease would likely destroy the implanted stem cells eventually.

Its unclear right now whether stem cell therapy could be used multiple times to continue to reduce symptoms of Parkinsons disease or if the effect would be the same after multiple procedures.

Until the discovery of the process of creating iPSCs, the only stem cell therapies for Parkinsons disease required the use of embryonic stem cells. This came with ethical and practical challenges, making research more difficult.

After iPSCs became available, stem cells have been used in clinical trials for many conditions involving neural damage with overall mixed results.

The first clinical trial using iPSCs to treat Parkinsons disease was in 2018 in Japan. It was a very small trial with only seven participants. Other trials have been completed using animal models.

So far, trials have shown improvement to symptoms affecting movement as well as nonmotor symptoms such as bladder control.

Some challenges do arise from the source of the stem cells.

Stem cell therapy can be thought of as being similar to an organ transplant. If the iPSCs are derived from a donor, you may need to use immunosuppressant drugs to prevent your body from rejecting the cells.

If the iPSCs are derived from your own cells, your body might be less likely to reject them. But experts believe that this will delay stem cell therapy while the iPSCs are made in a lab. This will probably be more costly than using an established line of tested iPSCs from a donor.

There are many symptoms of Parkinsons disease. Theyre often rated using the Unified Parkinsons Disease Rating Scale (UPDRS) or the Movement Disorder Societys updated revision of that scale, the MDS-UPDRS.

Clinical trials today are generally looking to significantly improve UPDRS or MDS-UPDRS scores for people with Parkinsons disease.

Some trials are testing new delivery methods, such as intravenous infusion or topical applications. Others are looking to determine the safest number of effective doses. And other trials are measuring overall safety while using new medical devices in stem cell therapy.

This is an active area of research. Future trials will help narrow down the most safe and effective approach to stem cell therapy for Parkinsons disease.

Clinical trials are usually conducted in three phases. Each phase adds more participants, with the first phase usually limited to a few dozen people and several thousand in the third phase. The purpose is to test the treatments safety and effectiveness.

Clinical trials testing stem cell therapy for Parkinsons disease are still in the early phases. If the current trials are successful, it will likely still be 4 to 8 years before this treatment is widely available.

The goal of stem cell therapy for Parkinsons disease is to replace destroyed brain cells with healthy, undifferentiated stem cells. These stem cells can then transform into brain cells and help regulate your dopamine levels. Experts believe this can relieve many of the symptoms of Parkinsons disease.

This therapy is still in the early stages of clinical testing. Many trials are either proposed, currently recruiting, or already active. The results of these trials will determine how soon stem cell therapy might become widely available as a treatment for Parkinsons disease.

At the moment, its not believed that stem cell therapy will cure Parkinsons disease. But it might be an alternative to existing treatments such as drug therapies and deep brain stimulation.

Read the original:
Stem Cell Therapy for Parkinson's: Current Developments - Healthline

Recommendation and review posted by Bethany Smith

Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. Especially, cell sheet technology has been developed and has already been introduced to clinical situation. As the first step in development of cell sheet, neonatal cardiomyocyte sheets were established and these sheets showed electrical and histological homogeneous heart-like tissue with contractile ability in vitro and worked as functional heart muscle which has electrical communication with recipient myocardium in small animal heart failure model. Next, as a preclinical study, noncontractile myoblast sheets have been established and these sheets have proved to secrete multiple cytokines such as HGF or VEGF in vitro study. Moreover, in vivo studies using large and small animal heart failure model have been done and myoblast sheets could improve diastolic and systolic performance by cytokine paracrine effect such as angiogenesis, antifibrosis, and stem cell migration. Recently evidenced by these preclinical results, clinical trials using autologous myoblast sheets have been started in ICM and DCM patients and some patients showed LV reverse remodelling, improved symptoms, and exercise tolerance. Recent works demonstrated that iPS cell-derived cardiomyocyte sheet were developed and showed electrical and microstructural homogeneity of heart tissue in vitro, leading to the establishment of proof of concept in small and large animal heart failure model.

Therapeutic treatments using cells or cell-based tissues have been developed to regenerate the damaged myocardium associated with ischemic heart disease. This technique has already been evaluated in the clinical setting, using myoblasts [1] or bone marrow mononuclear cells (BM-MNCs) [2]. Although these studies demonstrated the feasibility and safety of this approach, the efficacy associated with this technology was generally insufficient to repair severe myocardial damage. Thus, a second generation of myocardial regenerative therapy, tissue-engineered cardiomyoplasty, is currently being developed. A large number of achievements concerning basic, preclinical, and clinical works about cell sheet technology have been done and this review summarizes recent advances in myocardial regeneration emerging from the development of cell sheet technology.

Cell-sheet techniques have been applied to several diseased organs, such as the heart [3], eye [4], and kidney [5], in the laboratory and the clinic. Cell sheets can be prepared on special dishes that are coated with a temperature-responsive polymer, poly(N-isopropylacrylamide) (PIPAAm), that changes from being hydrophobic to hydrophilic when the temperature is lowered. This change allows cells to be removed without EDTA or enzymatic treatment and without destroying the cell-cell or cell-extracellular matrix (ECM) interactions within the cell sheet.

Shimizu et al. used such temperature-sensitive culture dishes to develop a contractile chick cardiomyocyte sheet that exhibited a recognizable heart tissue-like structure and showed electrical pulsatile amplitude [6]. Next, they layered single-cell sheets to generate bilayer-cell sheets, forming an electrically communicative three-dimensional cardiac construct, which exhibited spontaneous and synchronous pulsation with electrical communication between the cell sheets, mediated by connexin 43. Furthermore, the cell sheets adhered together rapidly, as indicated by the presence of desmosomes and intercalated disks between them [7]. When the pulsatile cardiac tissue was implanted subcutaneously, it was found to assume a heart tissue-like structure and exhibited neovascularization and spontaneous beating for up to one year. The size, conduction velocity, and contractile force of the engrafted sheets increased in proportion to the host growth [8, 9].

Miyagawa et al. demonstrated that a neonatal cardiomyocyte sheet could communicate electrically with the host myocardium, as indicated by the presence of connexin 43, and changes in the QRS wave and action potential amplitude, leading to improved cardiac performance in a rat model of ischemic heart disease [3]. This study clearly showed electrical and morphological coupling between the cell sheet and host myocardium and that the cell sheet could contract synchronously with the beating of the host heart and improve the regional systolic function.

A detailed analysis of the vascularization process following cell sheet implantation was undertaken by Sekiya et al. These authors reported that the cardiomyocyte sheet expresses angiogenesis-associated genes and forms an endothelial cell network. Evidence was also presented suggesting that the vessels arising in the engrafted sheet migrate to connect with the host vasculature [10].

Myocardial tissue grafts engineered with cell sheet technology represent a promising therapy for repairing the damaged myocardium, but there may be some inherent limitations. For example, cellular treatment for heart failure may be not suitable for emergency situations. Another issue is that wide therapeutic use will require improvement in the uniformity in the quality of the cultured cells.

Recently, new medications that imitate the paracrine effects of cytokines in cell sheets have been reported, and the addition of such medications could improve the regenerative treatment for heart failure. It was reported that the direct introduction of a prostacyclin agonist into the damaged myocardium induced significant functional recovery in a canine model of dilated cardiomyopathy, via the upregulation of multiple cytokines, including HGF, VEGF, and SDF-1 [11]. Similarly, the implantation of an atelocollagen sheet containing a prostacyclin analogue induced improved cardiac function and a prolonged survival rate in a mouse model of acute myocardial infarction, accompanied by an enhanced expression of SDF-1 [12]. Recent work has also revealed that prostacyclin may be upregulated in the implanted myoblast sheet in the early phases after implantation in response to ischemic conditions and may in turn stimulate endothelial or smooth muscle cells to secrete multiple cytokines including HGF, VEGF, and SDF-1 (data not shown).

In the clinical setting, cellular cardiomyoplasty is reported to have potential regenerative capability, and a method using skeletal myoblasts has been evaluated in clinical trials and found to be relatively feasible and safe [13]. For tissue cardiomyoplasty, skeletal myoblasts are the cell source closest to being ready for clinical application at this time. Memon et al. demonstrated that the nonligature implantation of a skeletal myoblast sheet into a rat cardiac ligation model regenerated the damaged myocardium and improved global cardiac function, by attenuating cardiac remodeling via hematopoietic stem-cell recruitment and growth-factor release, with better restoration of the implanted cells than that obtained using needle injection [14]. In another study, the application of a skeletal myoblast sheet into a 27-week dilated cardiomyopathy hamster model resulted in the attenuated deterioration of cardiac performance accompanied by the preservation of alpha-sarcoglycan and beta-sarcoglycan expression in the host myocytes, and an inhibition of fibrosis, leading to prolonged survival rates [15]. In addition, the grafting of skeletal myoblast sheets attenuated cardiac remodeling and improved cardiac performance in a pacing-induced canine heart failure model [16]. Studies from our group have shown that myoblast sheets may improve cardiac performance via cytokines such as HGF or VEGF (XX).

The mechanism of recovery in the damaged myocardium has not been completely elucidated and may be very complicated. As mentioned above, cytokine release and hematopoietic stem-cell recruitment are possible mechanisms of regeneration; however, other regenerative mechanisms are likely to be involved as well. Skeletal myoblasts cannot beat synchronously with the host myocardium in vitro [17] or in vivo [18], and, thus, they do not appear to be functionally integrated. However, data from our human and porcine studies suggested that after myoblast sheet implantation, the diastolic dysfunction in the distressed region of the myocardium was significantly recovered compared with controls, leading to improved systolic function in the same region, without contraction of the implanted myoblasts (data not shown). Massive angiogenesis in the implanted region was detected histologically and appeared to be a critical feature associated with the improvement. Thus, we speculate that angiogenesis and the recovery of diastolic function are both major components of the regenerative mechanism in myoblast sheet implantation [19].

On the other hand, immunohistochemical analysis has indicated that the myoblast sheet may only survive for a few months after implantation. We speculate that in the early phases after implantation of the myoblast sheet, the ischemic conditions induce the upregulated expression of several cytokines by the myoblasts that promote their own survival. These cytokines then in turn enhance angiogenesis and the recruitment of stem cells, leading to improved blood perfusion to reactivate the damaged myocardium. The system may continue to be effective in spite of the short-lived myoblast sheet, due to long-term maintenance of the newly developed vasculature.

We recently initiated a clinical evaluation of autologous myoblast sheet implantation. We tested the technology in four patients who were using left ventricular assist devises (LVADs); three of the four patients showed functional recovery, and in two of the patients, the treatment provided a bridge to recovery [20]. Six years later, these two patients have no symptoms of heart failure. We have also implanted myoblast sheets into eight patients with ischemic cardiomyopathy and seven with dilated cardiomyopathy (who were not using LVADs). In that study, some of the patients exhibited left ventricle reverse remodeling and improvements in exercise tolerance and symptoms, with no major adverse cardiac events (MACEs) (data not shown). This clinical research program is ongoing, as we continue to evaluate patients with dilated cardiomyopathy and ischemic cardiomyopathy with and without the use of LVADs.

In addition to cardiomyocytes and myoblasts, other types of cell sheets have been used effectively to improve cardiac performance. The transplantation of a mesenchymal stem cell (MSC) sheet onto the infarcted myocardium of rats resulted in increased anterior wall thickness and new vessel formation, accompanied by a low incidence of differentiation of the implanted cells to cardiomyocytes [21]. While the small number of differentiated cardiomyocytes may not have contributed to the observed improvement in systolic function in this study, the cell sheet exhibited self-propagating properties that promoted the generation of a thick-layered sheet. Although the MSC sheet exhibited a maximum thickness of approximately 600m, which would not be strong enough to correct human end-stage heart failure [22], this method of self-propagation is a potential strategy for creating a thick-layered sheet in vivo, with the potential for cardiac tissue regeneration.

A further development in cell sheet technology is the creation of a cell sheet composed of two types of cocultured cells; this type of cell sheet was developed to enhance angiogenesis [23, 24]. The cocultured cell sheet, which combined fibroblasts and endothelial progenitor cells, enhanced blood vessel formation and led to functional improvement in a rat myocardial infarction model [24]. Cocultured cell sheets combining fibroblasts and human smooth muscle cells were found to accelerate the secretion of angiogenic factors in vitro and to increase blood perfusion in vivo by the formation of new vessels [25]. This enhanced effectiveness attained by coculturing two cell types is supported by another study in which the coimplantation of BMCs and myoblasts showed improved results compared to the transplantation of a single cell type in a canine model of ischemic cardiomyopathy [26].

Cell sheets composed of stem cell antigen-1- (sca-1-) positive, or kit-positive cells may represent additional promising approaches. Matsuura et al. demonstrated that sca-1-positive cell sheets could differentiate into cardiomyocytes in vivo and produce VCAM-1, leading to improved cardiac performance in a mouse model of myocardial infarction [27]. The administration of c-kit-positive stem cells has shown efficacy in animal models of cardiac dysfunction, and this approach is currently being tested in clinical trials in combination with coronary artery bypass grafting, with encouraging preliminary results [28]. In another study, a c-kit-positive cell sheet combined with endothelial progenitor cell injection was found to induce better functional recovery of endocardial scar tissue than that induced by the cell sheet alone, despite the poor transdifferentiation ability of the c-kit-positive cells into cardiomyocytes [29].

Many of the cell sources mentioned above demonstrate regenerative ability based on the paracrine effect of secreted cytokines; however, newly differentiated cardiomyocytes may be the best candidate cells to regenerate the damaged myocardium. In 2006, Takahashi and Yamanaka reported the development of induced pluripotent stem (iPS) cells that can differentiate into various types of cells, such as cardiomyocytes, cartilage, and nerve cells [30]. Since then, there have been many reports showing that cardiomyocytes derived from iPS cells demonstrate electrophysiological, functional, and microstructural similarities to native cardiomyocytes [31]. Cardiomyocyte sheets derived from human or mouse iPS cells that contract synchronously in vitro have been developed, and studies indicate that these cardiomyocyte sheets can contract in vivo as analyzed by X-ray diffraction with synchrotron radiation. The transplantation of these sheets leads to functional recovery with upregulated electrical potential in the scarred areas in large [32] and small animal myocardial infarction models [33].

Although preclinical studies appear promising, the safety of these artificially generated cells must be evaluated thoroughly before they can be used in the clinic. In addition, a potential limitation of iPS cell-derived cardiomyocytes may be the loss of cardiomyocytes due to ischemia after implantation. Recent studies have proposed supplemental strategies to avoid ischemia. In one study, the combination of an iPS-derived cardiomyocyte sheet with omentum, which has a rich vasculature network, resulted in retention of the implanted cardiomyocytes and enhanced functional recovery compared with the cardiomyocyte sheet alone [34]. In another study, the transplantation of a cardiomyocyte sheet containing iPS cell-derived endothelial cells led to enhanced functional recovery in a rat myocardial infarction model and increased survival of the implanted cardiomyocytes [35]. Thus, to successfully treat the severely damaged myocardium using iPS cell-derived cardiomyocyte sheets, additional strategies to increase angiogenesis and reduce ischemia may be required.

Studies on the original myoblast cell therapy, in which cells were directly injected into the myocardium, indicated that the proportion of injected cells surviving to engraft the infarcted myocardium was too low to be effective. This low level of engraftment may have been caused by the injected cells leaking out of the injected region and being carried to other organs, or due to mechanical stress resulting in cellular loss of function. The resulting rapid cell loss [14] limited the usefulness of the original myoblast cell therapy.

To overcome the problems associated with the intramyocardial injection of cells, many investigators have combined cell transplantation with protein or gene therapy [36], or with tissue-engineered techniques [3]. We have also developed a new cell delivery system that uses tissue-engineered myoblast grafts grown as cell sheets and have utilized animal studies to guide clinical trials. These studies showed that the viability of the transplanted cells was higher than that of injected cells, and that the transplanted myoblasts survived for at least 3 months in the cardiac tissue of a porcine model of heart failure treated with autologous myoblast sheets. Using tissue-engineered temperature responsive techniques, we found that the implanted cells could be applied in larger numbers, were viable during transplantation, and were not lost from the applied region. Furthermore, we showed that cell sheets could be engrafted onto the failed myocardium and contribute to the attenuation of cardiac dysfunction and remodeling [14].

In cell therapy for cardiac disease, life-threatening adverse events involving arrhythmogenicity are a potential risk in both animal models and human clinical trials [37]; however, life-threatening arrhythmias have not been observed during the clinical course of patients who have received autologous cell sheet transplants. In any case, arrhythmias can occur during the natural clinical course of severe heart failure, so their cause may not be easily determined. Procedures using needle injection may cause scars in the myocardium that could in turn induce arrhythmias. Our cell delivery techniques using cell sheets prepared on temperature-responsive culture dishes may carry less risk for the induction of arrhythmias. Myoblasts have a weak electrical potential, and it may be possible for these cells to induce arrhythmia if they survive in the myocardium. However, cell sheets may not be able to induce arrhythmia, since they are attached to the epicardium.

Another potential problem is the limited blood perfusion to the implanted cell sheets. Although the survival of implanted cells using the cell sheet technique has already been shown to exceed the cell survival using other delivery routes, the survival rate was still found to be relatively low when the cells were implanted on the epicardium with this technique [38]. Although we have reported that improved cardiac performance depends on the dose of implanted myoblast sheets, the use of too many cell sheets results in a reduced blood supply. Thus, additional strategies, such as combining myoblasts with angiogenic factors [36] or other types of cells [23] to establish a vasculature network, may be needed to solve this problem. One strategy discussed above, is the combination of a myoblast sheet with omentum tissue that has a rich vasculature network. One report recently demonstrated the effectiveness of this approach for retention of the implanted cell sheets [39]. This report also suggested that the implanted myoblast sheet might induce vasculature connections between arteries of the transplanted omentum and the native coronary arteries, suggesting the possibility of biocoronary artery bypass grafting. This method may also be used in conjunction with iPS cell-derived cardiomyocytes to generate an artificial thick cardiac structure with increased vascular connections.

In this review, we surveyed many exciting topics in the area of cell sheet technology for cardiac repair. Owing to these studies, some techniques have already been tested in clinical applications, but the mechanisms by which they improve cardiac function are only partially understood, and much of the technology is still in the early stages of development, both experimentally and in the clinic. Nevertheless, the field of clinical myocardial regenerative therapy holds much promise, and we expect to witness more progress in this innovative technology in the near future.

The authors declare that there is no conflict of interests regarding the publication of this paper.

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