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Thread: What is the difference between embryonic and adult stem cells?

  1. #1

    What is the difference between embryonic and adult stem cells?

    This article appeared in the Rochester Democrat and Chronicle. Here are some comments on the questions and the answers that the article provides.

    http://www.rochesterdandc.com/apps/p...0361/1002/NEWS
    Question: What is the difference between embryonic and adult stem cells?

    Answer: Stem cells found in the embryo are cells that have the potential to turn into any of the organs or tissues in the human body. Adult stem cells have been found in certain tissues and have the potential to develop into that specific tissue. Some scientists say there is new evidence that specific adult stem cells might also have the ability to develop into other tissues.

    Question: Why do so many scientists want to focus on embryonic cells?

    Answer: Scientists say that, in addition to the potential to turn into any organ or tissue in the body, embryonic stem cells replicate more quickly than adult stem cells.
    Much effort is now being spent trying to find ways to grow adult stem cells. It turns out that it is neither easy or reliable to do so. My laboratory has been working on this problem over the past 2 years ago and I can say that a lot of claims cannot be easily replicated. Adult stem cells are not easy to isolate, grow, or expand. Studies of adult stem cells in skin and bone marrow now suggest strongly that adult stem cells usually do not act alone but rather they act in partnership with several other cells, in what are called "niches" where they need signals from other cells in order to produce certain types of cells. This is not surprising since the adult body does not want its stem cells to be producing all sorts of cells willy-nilly and the behavior of stem cells are rigorously controlled. We do not know yet all the signals nor methods to isolate, grow, and expand adult stem cells reliably. Lest people question this, I would just like to point out that if we were able to grow new blood cells in culture, we would no longer have to collect blood from people, store the blood in banks, throw out a lot of blood because they may be contaminated with diseases such as HIV and hepatatis, and then transfuse them into people. We are continuing to do so because this 80-year old technique is still the only way that we have of providing blood cells to people who need them. Likewise, if we were able to isolate and grow islet cells that can make insulin, hematopoietic stem cells, neural stem cells, and other cells from adult stem cells, we would be able transplanting these into patients. These cells are not yet available and we need to invest in research to make this approach to stem cell therapies become reality.

    uestion: What about stem cells found in umbilical cord blood?

    Answer: Those stem cells are considered adult stem cells because they come from infants, not embryos. Cord blood transplants have been done since the late 1980s to treat blood disorders. Other research is under way to determine whether cord blood can cure nonblood-related ailments. Researchers at Duke University recently used cord stem cells to treat babies with the fatal nerve disorder Krabbe's disease.
    Umbilical cord blood does indeed have cells that can become hematopoeitic stem cells. A recent reports does suggest that Krabbe's disease can be treated with umbilical cord blood. This is a neurodegenerative disease of infancy where cells do not make an enzyme that breaks down galactocerebroside. The consequent accumulation of galactocerebroside causes causes demyelination. Apparently, umbilical cord blood stem cells can reverse the symptoms in this almost invariably fatal disease (http://www.whonamedit.com/synd.cfm/1457.html).

    Question: Has stem cell research found any cures?

    Answer: Adult stem cells found in bone marrow have been used for years in the treatment of leukemia, lymphoma and other blood disorders. But while there are constant reports about progress in research, no standard of treatment has been created that calls for the use of stem cells.
    In the coming months, there will be papers reporting that umbilical cord blood transplants can cure thalessemia and sickle cell anemia.

    Question: Will New York fund stem cell research?

    Answer: Assembly Speaker Sheldon Silver, D-Manhattan, introduced a bill in March that would give $300 million over two years to a statewide stem cell research institute. State Sen. Nicholas Spano, R-Yonkers, offered a bill in June that would also fund stem cell research for $125 million over two years. But state politicians have not seemed interested in debating the issue until it is resolved at the federal level.
    Clearly, the resolution of the federal issue is important for everybody. The feeling is that the state should not be funding the research and that this is the responsibility of the federal government.

    Question: How would the University of Rochester be affected if embryonic research isn't funded in New York state?

    Answer: That answer is still unknown. UR officials say it will have a tremendous impact because some of their 18 adult stem cell researchers are getting calls from other states to do embryonic research there. California is the biggest draw, giving $3 billion to stem cell research over 10 years. UR says its stem cell researchers bring in $42 million in grants each year.
    Many other universities in New York are affected. At the present, New York researchers are handicapped when it comes to doing human stem cell research. They must rely on private funds when it comes to doing research on embryonic stem cells other than the 22 or so stem cell lines that have been approved by the Federal government.

    Question: Will embryonic research lead to cloning?

    Answer: U.S. officials have been clear about their interest in banning reproductive cloning of human beings if embryonic research is allowed to go forward. Reproductive cloning would entail producing a cloned embryo of a person and implanting it in a woman so it can be born. Therapeutic cloning, which is what scientists want to pursue, would entail cloning a patient's cells so they could eventually be used to replace damaged cells.
    Congress is now segregating the issue of human embryonic stem cell research and therapeutic cloning. At the present, there are probably over 120 human embryonic stem cell lines that are not cloned but NIH is not allowed to fund research on all but 22 of these lines. The current HR810 bill in Congress proposes to allow NIH to fund research on these new embryonic stem cell lines. The cloning issue is being considered in a separate bill which defines cloning as the creation of a blastocyst that is then transplanted into a uterus for development. If passed, such cloning (or reproductive cloning) would be illegal while therapeutic cloning or the creation of stem cell lines from cloned blastocysts would be allowed.

  2. #2
    Dr. Young,

    You say we do not yet know the signals necessary to reliably isolate, grow, or expand adult stem cells. Could you comment on how this lack of knowledge impacts the potential use of embryonic stem cells in future therapies? Specifically, how many of the 200+ cell types that make up the human body do we know how to grow from ESCs? Supposing ESCs will likely be pre-differentiated prior to transplantation (I assume to precursors or ASCs, or precursors of ASCs), how efficient is the current technology at growing and isolating a desired cell type?

    Thanks.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  3. #3
    Wise, could there be a way to obtain ESCs at "one step remove" from actual embryos? (As in cells grown "on" something else?) Is that what you are describing?

    Example: I was recently at a conference in which people showed interest in a mushroom thought to be therapeutic (cordyceps), yet they are naturally grown on the backs of caterpillars. The vegans therefore objected to mass-marketing this, so figured out how to grow the mushrooms in soy protein instead, but the active ingredient is (apparently) far less potent.

    I was wondering: any way to replicate something like that for ESC?

    How about from tissue taken from an embryo that is not killed, as in prenatal surgery? Or is it just too small to even attempt that?

    Thanks for your input, and thanks for the article.
    Last edited by MrSoul; 07-25-2005 at 07:56 AM.
    "Who are all these strange ghosts rooted to the silly little adventure of earth with me?"--Jack Kerouac

  4. #4
    Steven, let me go describe the differences systematically in three situations: culturing the cells, transplanting the cells into adult tissues, and transplanting the cells into developing fetuses.

    Culturing stem cells. Scientists can now grow embryonic stem cells in quantity without feeder cells. The cells that were isolated in 1997 by Jamie Thompson from Wisconsin are still growing in 2005. In contrast, scientists have been trying to grow mesenchymal stem cells from bone marrow for decades. Certain cells from bone marrow will grow for 30-40 passages (9 months or so) and then stop. We recently found that we can grow stem-like cells from umbilical cord blood for as long or longer. However, both umbilical and adult stem cells take a long time to start grow, often just floating for weeks or months before they attach and start to divide. Also, probably about 75% of the time, when you try to grow the cells from a given sample, nothing grows out. While this is not so different from embryonic stem cells which can be successfully grown from perhaps 1 out of 4 blastocyst, once an embryonic stem cell line is establish, you can reliably grow that cell line every time and for many years. Harvesting bone marrow stem cells from a person and growing stem cells is not yet a slam dunk. A lot of times, you get cells that you don't want or are not stem cells. Growing adult and umbilical cord blood cells is still an art, not yet a science.

    Differentiation in culture and when transplanted into adult tissues. If you grow embryonic stem cells in serum, they will spontaneously produce a variety of cells, from astrocytes to neurons, blood cells, bone, cartilage, etc. Using retinoic acid and sonic hedgehog, scientists can reliably grow astrocytes, oligodendroglia, and neurons, including motoneurons, inhibitory and excitatory interneurons that express gaba/glycine and glutamate from embryonic stem cells. In fact, if you don't pre-differentiate embryonic cells and transplant them into adult animals, they will often form teratomas or tumors that have all the different kinds of cells of the body. This usually happens if you put in a bolus of embryonic stem cells into the tissue and they can interact with each other. By contrast, bone marrow and umbilical cord blood cells have to be grown in serum and they do not readily differentiate into neurons, astrocytes, or other kinds of cells in culture. You have to push them and grow them for a long time and occasionally a cell will arise in culture that look like neuron or some other kind of cell. When you transplant bone marrow or umbilical cord blood cells into the spinal cord, usually they do not migrate and they don't do much at all. If you transfuse umbilical cord blood cells, it takes several weeks or months but some of the cells find their way into hematopoietic "stem cell niches" that are present in the body and can produce blood cells. There are of course also many reports of microchimerism in mothers where fetal cells have crossed the placental-maternal barrier and have settled into various stem cell niches all over the body. We have been studying all these phenomenon and find that it is a haphazard phenomenon.

    Transplantation into developing fetuses. During development, presumably all the signals for differentiation are present. Therefore, many investigators have transplanted putative stem cells into developing fetuses. When you transplant embryonic stem cells into a developing mouse fetus, you will see the cells with the transplanted marker present in almost all tissues of the mouse when it is born. This use to be the gold standard for demonstrating pluripotency and embryonic stem cell lines are tested in this fashion. However, several years ago, scientists discovered that transplanted cells may fuse with other cells. Thus, for example, all the early reports that bone marrow stem cells can produce neurons when transplanted into fetuses turn out to be the bone marrow cells fusing with stem cells from the fetus. Ira Black recently reported that when he transplanted bone marrow stem cells into the brain, he found some of the cells growing into neurons.

    So, in summary, embryonic stem cells are spontaneously pluripotent and they can do it by themselves. Also, we can reliably differentiate embryonic stem cells into neurons and most of the cells of the central nervous system. I don't know anybody who has tried to create olfactory ensheathing glial cells from embryonic stem cells yet but I expect that this will happen soon. In contrast, adult stem cells need signals that we do not yet understand. Recent studies suggest that adult stem cells act in consortium with other cells, in "stem cell niches" that exist in many tissues. If the transplanted cells find their way into these niches, they can produce appropriate cells for specific tissues. Much progress is being made in this area and I am confident that better methods will be available for isolating adult stem cells. For example, just in San Franscisco, one group identified the SLAM familiy of markers, combinations of which can be used to identify hematopoietic stem cells.

    Wise.

    Quote Originally Posted by Steven Edwards
    Dr. Young,

    You say we do not yet know the signals necessary to reliably isolate, grow, or expand adult stem cells. Could you comment on how this lack of knowledge impacts the potential use of embryonic stem cells in future therapies? Specifically, how many of the 200+ cell types that make up the human body do we know how to grow from ESCs? Supposing ESCs will likely be pre-differentiated prior to transplantation (I assume to precursors or ASCs, or precursors of ASCs), how efficient is the current technology at growing and isolating a desired cell type?

    Thanks.
    Last edited by Wise Young; 07-25-2005 at 10:30 AM.

  5. #5
    Quote Originally Posted by MrSoul
    Wise, could there be a way to obtain ESCs at "one step remove" from actual embryos? (As in cells grown "on" something else?) Is that what you are describing?

    Example: I was recently at a conference in which people showed interest in a mushroom thought to be therapeutic (cordyceps), yet they are naturally grown on the backs of caterpillars. The vegans therefore objected to mass-marketing this, so figured out how to grow the mushrooms in soy protein instead, but the active ingredient is (apparently) far less potent.

    I was wondering: any way to replicate something like that for ESC?

    How about from tissue taken from an embryo that is not killed, as in prenatal surgery? Or is it just too small to even attempt that?

    Thanks for your input, and thanks for the article.
    MrSoul,

    I am not sure that I understand your question but let me try to answer it as best as I can. There have been many attempts to figure out ways to get embryonic stem cells without involving an embryo. Most of these have not been satisfactory (at least for me and I suppose also for opponents of embryonic stem cell research). Let me summarize some of these.

    1. Incapacitated eggs. Hurlburt suggested the use of eggs that are genetically modified so that they cannot grow beyond the blastocyst stage. Woo-suk Hwang pointed out that his cloned blastocysts cannot grow beyond the blastocyst stage even if they wanted to do it and, particularly if they were not transplanted into the uterus. Therefore, what is the difference between what Hurlburt is suggested and what Woo-suk Hwang is doing?

    2. Egg-like cells from embryonic stem cells. It may be possible to grow egg-like cells from embryonic stem cells, transfer nuclei to them, and get them to grow out stem cell lines. Several groups have reported success in growing egg-like cells from embryonic stem cells or even fetal stem cells and these egg-like cells can be fertilized and grown for a period. So far, I don't think that anybody has successfully grown a stem cell line from such cells. On the other hand, scientists have long been able to produce transgenic mice from embryonic mouse stem cells.

    3. Fusion of embyronic and adult stem cells. Stem cells like to fuse with each other. I know several groups that are working on fusing embryonic stem cells and umbilical cord blood stem cells. By mixing the two populations, some of the fused cells may behave like embryonic stem cells. I don't know yet how successful this work is but it is a very intriguing idea and, if it works, it may circumvent the need for an embryo to create new embryonic stem cell lines.

    4. Removing several cells from a fertilized embryo. Several in vitro fertilization clinics are removing single or multiple cells from blastocysts to do genetic testing. They claim that this can be done without harming the blastocyst. I must say that I am skeptical. If the blastocyst is harmed by the removal of the cells, the blastocyst simply will not implant and survive. While this eliminates the problem of having a deformed baby, it may still kill some blastocysts. But, more important, many people oppose this approach because it is really part of the procedure of selecting blastocysts based on their genes. Finally, I don't know anybody who has been able to grow a stem cell line from several cells removed from the blastocyst. Note that it is hard enough to grow stem cells from blastocysts even if one used all the 200 or so cells of the inner cell mass.

    One or more of these methods may produce human embryonic stem cell lines without involving a human embryo. By the way, a blastocyst is generally not considered an embryo and that is why I can make the statement. If one were to consider a blastocyst an embryo, than the first two of methods would not be acceptable. I am concerned with the time that it would take. It may be years before any of these methods will yield enough stem cell lines with sufficient diversity for therapeutic purposes. At the present, it is estimated that there have probably been about 120 or so human embryonic stem cell lines that have been isolated from in vitro fertilized eggs that would otherwise be thrown away. NIH will fund scientists to study about 22 of these lines (all derived before 2001). But scientists, such as myself, would not be allowed to use NIH funds to study the 17 cell lines derived last year by Douglas Melton at Harvard or the 12 human stem cell lines, produced by Woo-suk Huang by transferring nuclei into eggs this year.

    It is very likely that we will soon discover the gene(s) that make embryonic stem cell immortal without turning them into tumors. It should be possible to create adult stem cell lines that can grow for long times. Already several oncogenes are now routinely used in animal studies to "immortalize" stem cells. For example, a colleague in the Keck Center uses V-myc to immortalize fetal stem cells and the cells do not become tumors when transplanted. Acceptance of such genetically manipulated cells and demonstrating their safety, however, may take a number of years before FDA would approve their use.

    Wise.
    Last edited by Wise Young; 07-25-2005 at 10:28 AM.

  6. #6
    I apologize for the typographical and grammatical errors in the posts but I am typing rapidly without editing. I will go back and correct them when I have time. I wanted to get the posts out. Sorry and thanks. Wise.

  7. #7
    Wise, thanks for the reply.

    Quote Originally Posted by Wise Young
    Differentiation in culture and when transplanted into adult tissues. If you grow embryonic stem cells in serum, they will spontaneously produce a variety of cells, from astrocytes to neurons, blood cells, bone, cartilage, etc. Using retinoic acid and sonic hedgehog, scientists can reliably grow astrocytes, oligodendroglia, and neurons, including motoneurons, inhibitory and excitatory interneurons that express gaba/glycine and glutamate from embryonic stem cells.
    Have any functional differences been described in the literature between neural types obtained from embryonic stem cells grown in different media (e.g., serum vs. retinoic acid and sonic hedgehog)?
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  8. #8
    Quote Originally Posted by Steven Edwards
    Wise, thanks for the reply.

    Have any functional differences been described in the literature between neural types obtained from embryonic stem cells grown in different media (e.g., serum vs. retinoic acid and sonic hedgehog)?
    Yes, you know some of them. In 1999, McDonald, et al., showed that embryonic stem cells will remyelinate the spinal cord and improve function. (Please note that bone marrow stem cells have also been shown to stimulate remyelination although more work needs to be done to show that the bone marrow stem cells themselves are producing the cells that remyelinate the axons). Several laboratories have shown that embryonic stem cells will actually produce oligodendroglia cells in the spinal cord and these cells will remyelinate. Likewise, the Johns Hopkins paper showed the mouse embryonic stem cells will produce motoneurons and when the transplants are combined with growth factors, will actually send axons out the spinal roots and improve functional recovery in rats that have had motoneuronal damage due to a virus. Many laboratories have now used dopaminergic cells produced from embryonic stem cells to treat Parkinson's disease in animals. I believe that it is only a matter of time before somebody will show that GABAergic and glycinergic (inhibitory) neurons produced from embryonic stem cells can inhibit neurons and can be used for the treatment of chronic neuropathic pain and also spasticity. This is just the tip of the iceberg.

    Several things have held back research in this area. The first is that nobody has yet successfully isolated and grown rat embryonic stem cell lines. Mouse embryonic stem cells have of course been grown and these are the cells that are being used to treat rat. Because these are species-to-species transplants, it is necessary to use prolonged immunosuppression in these studies. Therefore, long-term studies are relatively rare and difficult to carry out. Second, we still don't really understand why it is possible to grow mouse and human embryonic stem cells but not rat embryonic stem cells. It is also likely that there are major differences between mouse and human stem cells but there has not been enough work done on human embryonic stem cells in the United States to show what these differences are. Some laboratories (such as Keirstead) are beginning to transplant human embryonic stem cells (NIH lines) into rats with spinal cord injury. Third, only this year, scientists have discovered that BMP plays a major role in sustaining human embryonic stem cells in culture and have been able to grow the cells without mouse feeder cells.

    Wise.

  9. #9
    Thanks again, Wise. I apologize for phrasing my prior question poorly. Please allow me to try again.

    Have neural cell types obtained by culturing ESCs in serum been shown to be more (or less) effective in treating injuries than those obtained by culturing ESCs in RA and sonic hedgehog?

    Thanks for your patience.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  10. #10
    Quote Originally Posted by Steven Edwards
    Thanks again, Wise. I apologize for phrasing my prior question poorly. Please allow me to try again.

    Have neural cell types obtained by culturing ESCs in serum been shown to be more (or less) effective in treating injuries than those obtained by culturing ESCs in RA and sonic hedgehog?

    Thanks for your patience.
    I don't think that this experiment has been done recently. Since the reports came out that retinoic acid and sonic hedgehog will differentiate embryonic stem cells towards neural stem cells and precursors, almost all the studies that I have seen have used this approach to pre-differentiate the cells. By the way, most of the human embryonic stem cells that have been studied to date were all grown in serum and mouse feeder cells. I have not seen any experiments on injured spinal cords using the new non-feeder cell culture systems.

    Also, I was thinking that you might be interested in this article that just came out:

    http://www.marketwatch.com/news/news...iticstoday.com

    Georgia Reproductive Specialists: Atlanta Physician's Research Indicates New Source for Stem Cells
    7/25/2005 8:24:49 AM

    ATLANTA, July 25, 2005 /PRNewswire via COMTEX/ -- Dr. Eric Scott Sills, a physician with Georgia Reproductive Specialists (GRS), has completed a research study detailing new approaches to human embryonic stem cell harvesting. The manuscript, "Identification and isolation of embryonic stem cells in reproductive endocrinology: theoretical protocols for conservation of human embryos derived from in vitro fertilization," appears in the most recent issue of "Theoretical Biology and Medical Modelling," published by Biomed Central in London.

    Human embryonic stem cell research is controversial because the traditional methods used to acquire such cells render embryos nonviable and unsuitable for transfer in utero. The two techniques described by Dr. Sills and his colleagues are designed to be conducted in a way that does not destroy viable human embryos. The first approach shows how researchers can take normal cells out of embryos that would never be of sufficient quality to transfer in IVF or even freeze. The alternate approach suggests the biopsying of normal/healthy embryos and then taking that one individual cell to create a whole embryo identical to the first. In this method, the source embryo remains viable when the procedure is completed. Other members of the research team included Takumi Takeuchi, Noriko Tanaka, Queenie Neri and Prof. Gianpiero D. Palermo, all from Cornell University.

    "Stem cell research is certainly a critical, yet controversial, issue," said Sills, a former Cornell medical faculty member. "My colleagues and I have been working on strategies for stem cell harvest that do not harm human embryos. With our methods, stem cells can be made available for groundbreaking medical research and no embryos are damaged or destroyed in the process."

    The full manuscript is available online at the following address: http://www.tbiomed.com/content/pdf/1742-4682-2-25.pdf

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