2006 Articles
Due to copyright restrictions, the full text of articles linked below is available only to the NIH community. Those outside the NIH community can access citations and abstracts.
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- Scientists Generate Human Embryonic Stem Cell Lines from Naturally Dead Embryos
Scientists funded by the United Kingdom and other private sources announced that they have generated human embryonic stem cell (hESC) lines from in vitro fertilization (IVF) embryos that have stopped developing naturally. The human stem cells created using this technique behaved like pluripotent stem cells, including making proteins critical for "stemness" and being able to produce cells from all three germ layers. Proponents of this technique suggest that when an IVF embryo naturally dies, the embryo could not develop into a human being, and thus could potentially be used to derive human embryonic stem cells without having to destroy a living embryo. However, ethical considerations make it uncertain whether scientists will equate this procedure of deriving hESC lines to organ donation. That is, scientists can take live cells from dead embryos in the same way that doctors take live organs from individuals who have donated them after death. (Stem Cells 24:2669–2676, laboratory of M. Stojkovic)
- Small Molecule Important for Self-Renewal of Embryonic Stem Cells
Embryonic stem cell culture medium usually includes animal-derived products like serum that are impossible to standardize. Ideally, scientists would like to develop growing conditions that replace all animal products with drugs or other factors that can be standardized (see Drug Enables Stem Cells to Remain Pluripotent in Culture). Privately funded scientists have recently identified a small molecule (called SC1) that seems capable of replacing nonstandard animal products in mouse embryonic stem cell (ESC) cultures. When grown in medium supplemented with the small molecule, mouse ESCs demonstrated the standard characteristics of "stemness," including the ability to generate tissues from all germ layers and contribute to the embryo when injected into a mouse blastocyst. Tests indicate that the small molecule acts by simultaneously blocking the molecular pathway to ESC differentiation and activating self-renewal signaling processes. This discovery may help scientists develop defined growth conditions and understand the underlying molecular mechanisms that give stem cells their unique properties; it could ultimately help them develop human therapies. (Proceedings of the National Academy of Sciences of the USA 103:17266–17271, laboratory of S. Ding)
- Mouse Embryonic Stem Cells Help Save Mice with Liver Failure
Chronic liver diseases such as cirrhosis and hepatitis affect 25 million Americans. Although liver transplantation can help some of these individuals, there is an extreme shortage of transplantable organs. Scientists hope to overcome the organ shortage by using stem cells to replace lost liver function. A collaborative team of Japanese and NIH-funded scientists coaxed mouse embryonic stem cells into becoming liver-like cells. They used the new mouse liver-like cells in a bioartificial liver, an implanted device that uses liver cells to replace some liver function. Ninety percent of mice with liver failure that were implanted with the bioartificial liver survived, while mice with liver failure that did not receive the implant all died within two days. If scientists can repeat these results with human stem cells, the technique offers promise both to individuals born with liver problems and to those who develop liver disease later in life. (Nature Biotechnology 24:1412–1419, laboratory of I. Fox)
- Self-Replicating Insulin-Producing Cells Generated from Human Embryonic Stem Cells (hESCs)
One hopeful prospect for treating diabetes is to replace the damaged or missing insulin-producing beta islet cells in the pancreas. Unfortunately, the supply of transplantable pancreatic islets is unable to meet the demand. In an effort to find another source of insulin-producing cells, privately supported scientists have now succeeded in generating insulin-secreting cells from hESCs by allowing the cells to mimic pancreatic development. The scientists observed that hESCs grown under specific conditions can be guided to first develop into endoderm, the layer of embryonic tissue that gives rise to all the organs of the gut, including the pancreas, then to endocrine precursor cells. At this stage, the cells are capable of secreting all of the pancreatic hormones, insulin, glucogon, somatostatin, pancreatic polypeptide, and gherlin. These hESC-derived precursor cells have almost as much insulin as adult beta cells. However similar to fetal beta cells, when stimulated with glucose, these hESC-derived precursor cells react minimally, and do not secrete enough insulin. Human beta cells do not acquire this capability until after birth. If scientists succeed at getting these cells to secrete enough insulin in response to blood sugar levels in human beings, they may one day be useful for treating diabetes. (Nature Biotechnology advanced online publication, laboratory of Novocell Inc.)
- With Risk of Cancer, Human Embryonic Stem Cells (hESCs) Can Improve Motor Function in Rat Model of Parkinson's Disease
Successful treatment for individuals with Parkinson's disease (PD) will be achieved when scientists can adequately replace the human dopamine-producing nerve cells (dopaminergic neurons) lost in PD. In 2004, NIH-supported scientists were able to successfully derive dopaminergic nerve cells from hESCs listed on the NIH Stem Cell Registry (See A Step Closer to Stem Cell-Derived Treatment for Parkinson's Disease). Now, NIH-supported scientists have developed a more efficient technique to derive dopaminergic neurons from hESCs They have grafted these hESC-derived highly enriched dopaminergic neurons into the brains of parkinsonian rats. The cells were able to significantly improve motor function. However, after three months of transplantation, the scientists examined the brains of the rats and found that many of the grafts contained groups of undifferentiated cells that have become cancerous tumors. That is, the transplanted dopaminergic neurons had difficulty fully incorporating into their new environment. If scientists can understand how to regulate the growth of the hESC-derived dopaminergic neuron transplants, these cells may serve as a renewable source of replacement dopaminergic neurons to treat PD in humans. (Nature Medicine 12:1259–1268, laboratory of S. Goldman)
- SCNT Works Better in More Mature Differentiated Cells than Adult Stem Cells
Scientists know that adult stem cells are rare and are difficult to isolate from tissues and organs of the body. However, differentiated cells (that have formed into specialized, tissue-specific cells) are found in large numbers in every type of tissue in the body. Scientists previously demonstrated that the success of somatic cell nuclear transfer (SCNT) depends on the maturity, or differentiation, state of donor nuclei (see SCNT Works Better if Donor Nucleus is Less Mature). Now, NIH-supported scientists have shown that the SCNT efficiency increases as the maturity of the cell increases. The scientists compared SCNT in mouse hematopoietic (blood-forming) stem cells, hemopoietic progenitor blood cells, and granulocytes (a type of white blood cell), which are at three increasing levels of cell maturity. Their data demonstrate that SCNT using nuclei from the three types of mouse blood cells produced viable embryos at 4–8, 11, and 35 percent efficiency, respectively. If scientists can improve the SCNT efficiency using abundant hemopoietic or other differentiated tissue donor nuclei, they may one day be able to use these techniques in humans to produce patient-specific stem cells for use in creating tissue to repair damage and treat disease. (Nature Genetics 38:1323–1328, laboratories of X. Yang and T. Cheng)
Please note: This scientific article reports discoveries that differ from those reported in another scientific article summarized on this page. These differences do not invalidate either study but rather demonstrate that there is currently no scientific consensus on this research topic.
- Scientists Can Stop Skin Stem Cells from Maturing into Adult Skin Cells
Human skin is replenished by skin stem cells that differentiate into specialized types of skin cells continuously throughout life. NIH-supported scientists have found that the gene for transcription factor 3 or Tcf3 (a protein that regulates gene activity) is activated in adult mouse skin where stem cells are expected to be located. They also found it was activated abundantly in embryonic mouse skin. Now, in a mouse model which the Tcf3 gene can be turned on or off, NIH-supported scientists discovered that activating the gene prevents embryonic skin stem cells from maturing into the specialized adult cells of the skin, namely epidermis, sebaceous, and hair follicles. If this application can be transferred to human embryonic stem cells, it can have important implications in growing skin cells damaged by burns and skin cancer. (Cell 127:171–183, laboratory of E. Fuchs)
- Further Evidence that Human Embryonic Stem Cells May Help Treat Vision Loss
In 2004, privately funded scientists derived retinal pigment epithelium (RPE) cells from human embryonic stem cells (hESCs) listed on the NIH Stem Cell Registry and from hESCs derived using private funds (see Human Embryonic Stem Cells May Help Treat Vision Loss). Now, these scientists report that they used these cells in rats with a genetic eye disease similar to age-related macular degeneration (AMD) (PDF file; get Adobe Reader), a major cause of vision loss in persons aged 60 and older. After over a month of treatment with the RPE cells, visual acuity in the rats improved. If these cells can successfully restore vision and replace damaged cells in the retina in a stable and effective manner in other animal models of AMD, they may be developed as a possible treatment for human AMD. (Cloning and Stem Cells 8:189–199, laboratory of R. Lanza)
- Protein Responsible for Balancing Stem Cell Growth, Aging, and Cancer
The standard explanation for the biological consequences of aging is that older organs and tissues "wear out" and are unable to repair themselves. Perhaps the repairs cannot be made because the supply of regenerative stem cells decline with age. However, scientists have known that a certain protein, known as p16, in high levels reduces the risk of cancer. Now, three groups of NIH-supported scientists examining hematopoietic (blood-forming) stem cells, neural stem cells, and pancreatic islet cells have discovered that p16 increases dramatically in older tissues. The older stem cells do not "wear out" as previously thought. On the contrary, p16 actively interferes with the ability for stem cells to proliferate, thus reducing the risk that older stem cells might develop into cancerous tumors. These groups studied mice that lacked p16. In young animals, the p16 deficiency increased the risk of cancer. Yet in older animals, the lack of p16 encouraged the growth of the stem cell supply in all three tissue types. This result has significant implications for the tradeoff between controlling cancer and preventing aging. (Nature 443:448–452, laboratory of S. Morrison; Nature 443:421–426, laboratory of D. Scadden; Nature 443:453–457, laboratory of N. Sharpless)
- Scientists Generate Human Embryonic Stem Cell Lines from Single Cells
In 2005, privately funded scientists demonstrated that it was possible to remove a single cell from a pre-implantation mouse embryo and generate a mouse embryonic stem cell line (see Fertility Clinic Technique Modified to Derive Stem Cells). Now, these scientists report that they have successfully established human embryonic stem cell lines from single cells taken from pre-implantation human embryos. The human stem cells created using this technique behaved like pluripotent stem cells, including making proteins critical for "stemness" and being able to produce cells from all three germ layers. Proponents of this technique suggest that since it requires only one cell from the embryo, the remaining cells may yet be implanted in the womb and develop into a human being. Thus scientists could potentially derive human embryonic stem cells without having to destroy an embryo. However, ethical considerations make it uncertain whether scientists will ever test if the cells remaining after removal of a single cell can develop into a human being, at least in embryos that are not at risk for carrying a genetic disorder. (Nature advance online publication, laboratory of R. Lanza)
- Scientists Reprogram Adult Mouse Skin Cells by Adding Defined Factors
Scientists have previously reported being able to "reprogram," or turn back the clock on adult cells, to make them behave as embryonic stem cells (see Human Embryonic Stem Cells Can Reprogram Adult Human Cells). However, the previous method fused a human embryonic stem cell with an adult human cell, producing a hybrid cell with four copies of the cellular DNA (tetraploid) rather than the normal two copies (diploid). Recently, scientists funded by the Japanese government reported that they could reprogram adult mouse skin cells by engineering the cells to express four defined factors: Oct3/4, Sox2, c-Myc, and Klf4, and growing the cells using embryonic stem cell culture conditions. The four factors are known to be important for maintaining the "stemness" of embryonic stem cells. The scientists called the reprogrammed adult cells "iPS" for "induced pluripotent stem" cells. iPS demonstrated important characteristics of pluripotent stem cells, including expressing stem cell markers, forming tumors containing cells from all 3 germ layers, and being able to contribute to many different tissues when injected into mouse embryos at a very early stage in development. Scientists will now try to determine if human adult cells can also be reprogrammed using this method. (Cell 126:1–14, laboratory of S. Yamanaka)
- Signaling Molecules May Help Adult Brain Repair Itself Following a Stroke
Scientists who study the developing nervous system know that crosstalk between neighboring cells—called cell signaling—is critical. Neighboring cells use cell signaling proteins, in the form of either surface receptors or molecules that activate surface receptors, to organize themselves. Intramural scientists at the National Institutes of Health (NIH) tested whether cell signaling proteins are also important for survival of the nervous system’s stem cells later in life. When added to cultured neural stem cells, the cell signaling proteins helped them survive by preventing cell death. This mechanism for preventing cell death is the same as those used by cancer stem cells during tumor formation. When injected into the forebrains of normal adult rats, cell signaling proteins helped maintain a robust population of adult neural stem cells. Rats that had suffered a stroke (lack of oxygen to part of the brain) demonstrated a progressive decline in motor skills. When the rats were treated with injected cell signaling proteins, the scientists observed an increase in the number of dividing neural stem cells. They propose that the neural stem cells may have contributed to these rats’ gradual improvement in motor skills, which was not observed in rats that had suffered a stroke and were treated with a control solution. These studies highlight how cells use the same signaling proteins during normal development, cancer, and repair activities. The scientists plan to study how the signaling proteins helped the rats recover, with the goal of optimizing the use of signaling proteins to treat animal models of brain injuries such as stroke. These studies may one day help scientists develop an effective way to treat individuals who have suffered a stroke. (Nature 442:823–6, laboratory of R. McKay)
- Neurons Grown from Embryonic Stem Cells Restore Function in Paralyzed Rats
Scientists are using stem cells from a variety of sources to help animals with spinal cord injuries regain movement. Human embryonic stem cells have been coaxed into becoming a type of cells that repaired damaged spinal cord insulation called myelin (see Human Embryonic Stem Cell Derivatives Help Spinal-Cord-Injured Rats Regain Mobility). Human non-embryonic neural stem cells helped replace damaged rat spinal cord nerve cells and myelin (see Human Stem Cells Help Rats with Spinal Cord Injury). NIH-supported scientists now report that they can use mouse embryonic stem cells (mESCs) to make functional motor neurons. Motor neurons are nerve cells found within the spinal cord that send fibers called axons out of the cord to connect with leg muscles and other muscles used to move the body. When motor neurons in the spinal cord are damaged, so is the ability to move their connecting muscles. The scientists combined several critical techniques in order to coax the mESCs to become motor neurons, to overcome the axon-repelling molecules released by existing myelin, and to attract the motor neuron axons to the correct muscles. Previously paralyzed rats treated with the motor neurons were able to move their legs again, although they could not walk or grip with their feet as well as uninjured rats. Since these studies were done in rats, they are not yet ready to be tested in humans. However, this research gives scientists insight on how they might one day replace human motor neurons damaged by spinal cord injuries and motor neuron diseases such as Lou Gehrig's Disease (amyotrophic lateral sclerosis, or ALS) and spinal muscular atrophies. (Annals of Neurology 60(1)32–44, laboratory of D. Kerr)
- Nanog Reprograms Mouse Brain Stem Cells
Scientists previously demonstrated that human embryonic stem cells can "reprogram" adult cells to make them behave like embryonic stem cells (ESCs) (see Human Embryonic Stem Cells Can Reprogram Adult Human Cells), but the cellular mechanisms responsible for this process have not been known. Privately funded scientists in the UK now report that the reprogramming process in mice is more efficient when they engineer the stem cells to over-express Nanog, a gene important for maintaining stem cells' self-renewing properties. The scientists report a 200-fold increase in the number of reprogrammed (hybrid) colonies generated when mouse ESCs that over-expressed Nanog were fused with stem cells from mouse brain. However, the fused cells are tetraploid, meaning that they contain four copies of the cellular DNA rather than the normal two copies. This study demonstrates that Nanog plays an important role in reprogramming the mouse brain cells to a state of pluripotency. If these results can be repeated with human cells, they would represent a first step toward learning how to reprogram adult cells to behave as stem cells and directing them to become specific cell types for use in treating human beings. Scientists must still learn how to remove the extra set of cellular DNA without removing the stem-cell like characteristics. (Nature 441(7096):997–1001, laboratory of A. Smith)
- SCNT Works Better if Donor Nucleus is Less Mature
Scientists who use somatic cell nuclear transfer (SCNT) to create new embryonic stem cell (ESC) lines know that the process is very inefficient, and the majority of their attempts fail to establish a new line. A group of NIH-funded scientists hypothesized that low success is due to the use of more mature, or differentiated donor nuclei, wherein important developmental genes have already been switched off. More mature cells are also more likely to have made other modifications to their DNA via a process called methylation. In this process, a methyl group is added to the DNA on or near a specific gene, keeping that gene from being used to make a protein. The scientists hypothesized that efficiency could be increased by using non-embryonic stem cells, whose nucleus is less likely to have switched off developmental genes during differentiation or to have made other DNA modifications via methylation. Their data demonstrate that SCNT using nuclei from (non-embryonic) mouse neural stem cells produced new ESC lines with an average efficiency of 64%. When they compared SCNT using nuclei from normal mature mouse skin cells and mature mouse skin cells whose ability to carry out methylation was reduced, the methylation-reduced nuclei were three times more efficient for establishing ESC lines. These data demonstrate that the differentiation state and methylation state of donor nuclei are critical factors in determining SCNT-derived ESC line efficiency. If scientists can improve their efficiency for SCNT-derived ESC line creation, they may one day be able to use these techniques in humans to produce patient-specific stem cells for use in creating tissue to repair damage and treat disease. (Stem Cells 24:2007–2013, laboratories of A. Smith and R. Jaenisch)
Please note: This scientific article reports discoveries that differ from those reported in another scientific article summarized on this page. These differences do not invalidate either study but rather demonstrate that there is currently no scientific consensus on this research topic.
- Scientists Identify Molecular Mechanisms for "Stemness"
In order to fit inside the cell nucleus, our DNA is coiled around protein cores, called histones, like beads on a string. The cell can start the process of making a protein from the DNA (transcription) by uncoiling the DNA around a particular histone. Alternatively, cells can block transcription by preventing the DNA from uncoiling. On a molecular level, the accessibility of a particular stretch of DNA plays an important role in determining the cell's characteristics, by controlling which genes are active and which are inactive because they are inaccessible. Three recent reports have increased scientists' knowledge of how stem cells remain undifferentiated yet pluripotent—key characteristics of "stemness."
In one study, scientists observed that important developmental genes in mouse ESCs are blocked when a molecule, called a methyl group, is added to the histone core of the DNA—a process called methylation. Methylation at this site tends to prevent the DNA from uncoiling. At the same time, methylation of another part of the same histone tends to prepare the DNA to uncoil. The scientists called the opposing methylation patterns "bivalent domains." They suggest that bivalent domains keep the ESCs undifferentiated, yet ready to differentiate when needed.
Two related studies, one in mice and one in humans, describe how a group of proteins, called polycombs, block transcription factors that turn on, or activate, important developmental genes in embryonic stem cells (ESCs). By preventing activation of genes essential to further development, polycombs prevent the ESCs from differentiating. Scientists studying human ESCs (hESCs) noted that the same genes blocked by polycombs were simultaneously bound by transcription factors known to be essential for hESC pluripotency, such as Oct4, Sox2, and Nanog. Thus, the same genes are simultaneously blocked yet primed for activation.
All three reports noted that the same genes were being blocked by both methylation and polycombs, while simultaneously being primed for future action by either methylation or by transcription factors such as Oct4, Sox2, and Nanog. These reports have now identified portions of ESC DNA that scientists must study to understand the essentials of "stemness." All studies cite NIH support. Cell 125(2):315–26, laboratory of E.S. Lander; Cell 125(2):301–13, laboratory of R.A. Young; Nature advance online publication, laboratory of R. Jaenisch)
- Pluripotent Stem Cells Found in Adult Mouse Testicles
German scientists succeeded in coaxing adult mouse stem cells that normally produce sperm (spermatogonial stem cells, or SSCs) to instead behave in a manner similar to embryonic stem cells (ESCs). They accomplished this switch of fate by finding the elusive SSCs in mouse testicles and growing them in the laboratory under standard ESC culture conditions. Under those conditions, the cells made several proteins characteristic of ESCs. The scientists subjected the cells to critical tests for pluripotency, and their results suggest that the cells can become any type of cell in the body. As a result, the scientists named them multipotent adult germline stem cells (maGSCs). If scientists can find similar cells in human testicles, the cells could provide a new source of patient-specific stem cells, and could also provide more pluripotent cell lines for research. (Nature advance online publication, laboratory of G. Hasenfuss)
- Family of Proteins Keeps Human Embryonic Stem Cells Alive in Culture
Human embryonic stem cells (hESCs) are difficult to maintain in an undifferentiated state. If improperly cultured, these fastidious cells can differentiate or die. NIH-funded investigators have identified cell surface receptors that are vital to survival of hESCs. These receptors bind to a family of proteins called neurotrophins, which prevents cell death (apoptosis). After adding a mixture of three neurotrophins to hESC cultures, the scientists observed a 36-fold improvement in survival of single cells. Blocking the receptors for neurotrophins resulted in hESC apoptosis. This discovery could help scientists grow large batches of hESCs to study what factors make them differentiate into specific cell types for use in treating human diseases. (Nature Biotechnology advance online publication, laboratory of P. Donovan)
- Scientists Expand Mouse Blood-forming Stem Cells in the Laboratory
Bone marrow and umbilical cord blood contain blood-forming (hematopoietic) stem cells. Treatment for blood cancer or other serious blood disorders destroys the existing, faulty hematopoietic system. Doctors then transplant bone marrow or cord blood in order to generate a healthy hematopoietic system. Hematopoietic stem cells are difficult to maintain in laboratory culture, and scientists have had little success at coaxing the cells to multiply. NIH-funded scientists identified proteins being expressed during blood cell formation in a developing mouse embryo. By adding some of these proteins to the cell cultures, they were able to expand the number of mouse hematopoietic stem cells by 24- to 30-fold. If human versions of these proteins can stimulate multiplication in human hematopoietic stem cells, scientists may be able to generate more cells for treating human diseases. (Nature Medicine 12:240–245, laboratory of H. Lodish)
- Are Stem Cells Produced by Somatic Cell Nuclear Transfer Normal?
Animals produced by somatic cell nuclear transfer (SCNT), such as Dolly the sheep, tend to develop physical abnormalities and die prematurely. This tendency caused scientists to wonder if embryonic stem cells created by SCNT, such as those that may be created for tissue-matched human therapies, might also be abnormal. NIH-supported scientists compared mouse SCNT-derived embryonic stem cells to mouse embryonic stem cells created using the standard in vitro fertilization (IVF) method. The SCNT-derived stem cells demonstrated an equal ability to produce cells from any body tissue and did not demonstrate significant changes in gene regulation—that is, how much a gene is expressed. These studies of early stages of genetic control suggest that IVF and SCNT-derived mouse embryonic stem cells are equal in their potential. If these experiments can be repeated with human cells, scientists will be able to determine whether human embryonic stem cells produced by IVF and SCNT have an equal potential for human therapy. (Proceedings of the National Academy of Sciences of the USA 103:933–938, laboratory of R. Jaenisch)
- Mouse Stem Cell Study May Help Improve Human Breast Cancer Treatments
Scientists funded by the Australian and Canadian governments have identified a stem cell in mice that is capable of dividing to produce a complete, functional breast. Scientists may now study this stem cell to identify its unique "stem-ness" genes and try to identify similar breast stem cells in human tissue. Because mutated breast stem cells are believed to play a major role in breast cancer, identification of human breast stem cells may help scientists develop more effective treatments against breast cancer. This knowledge may also enable scientists to grow human breast tissue for reconstructive surgery. (Nature 439:84–88, laboratory of J. Visvader)
- Wisconsin Scientists Grow Human Embryonic Stem Cells without Animal Products
An important goal for scientists is to develop culture conditions to grow embryonic stem cells in defined medium (see Growing Human Embryonic Stem Cells without Animal Products). Now, scientists at the University of Wisconsin have met this goal. They derived two new human embryonic stem cell (hESC) lines in a completely defined medium, using only human products. hESCs grown in defined conditions are likely to be more applicable to clinical use than hESCs grown with animal products. The scientists describe each component of their culture system in detail, so that others may use it and improve upon it. (Nature Biotechnology advance online publication, laboratory of J. Thomson)
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