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2005 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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  • Human Embryonic Stem Cells Survive and Function in Mouse Brain
    Privately funded scientists injected human embryonic stem cells (hESCs) into the brains of embryonic mice. The injected hESCs were not yet "differentiated," meaning that they had not yet become a particular cell type. The scientists observed that the hESCs took cues from the mouse brain environment and differentiated into nerve cells and supporting cells typically found in the brain. The human nerve cells appeared to form active connections, known as synapses, with the mouse nerve cells. Mice with functioning human nerve cells and supporting cells provide a valuable model system for learning how the human brain develops and for testing drugs to treat human nervous system diseases such as Lou Gehrig's and Parkinson's disease. (Proceedings of the National Academy of Sciences of the USA 102(51):18644–8, laboratory of R. Gage)
  • Fertility Clinic Technique Modified to Derive Stem Cells
    Scientists have modified a technique pioneered by human fertility clinics—called pre-implantation genetic diagnosis, or PGD—to create new mouse embryonic stem cell lines. Traditionally, PGD is used to test for inherited diseases before an embryo is transferred into the womb of a woman undergoing in vitro fertilization. PGD requires scientists to remove one cell from a very early in vitro-fertilized human embryo and test it for diseases known to be carried by the sperm or egg donors. Proponents of the modified PGD technique—known as single cell embryo biopsy—suggest that since it requires only one cell from the embryo, the remaining cells may yet implant in the womb and develop into a living being. Privately-funded scientists removed single cells from early mouse embryos. Rather than testing the single cells for inherited diseases, they used them to establish mouse embryonic stem cell lines. The remaining cells of the embryo were implanted in surrogate mouse wombs and approximately half developed into seemingly normal mouse pups. In the control group of non-biopsied embryos, about half also developed to birth as normal pups. This research is the first to demonstrate that single cell embryo biopsy can be used successfully to generate stem cell lines. If this technique succeeds with human embryos, it may provide another way to generate human embryonic stem cell lines. Although single cell embryo biopsy proposes to avoid embryo destruction, scientists do not yet know how much risk the procedure might confer to an otherwise healthy human embryo. Additionally, it may be argued that the very early cell that is biopsied is in itself capable of developing into a living being. (Nature 439:216–219, laboratory of R. Lanza)
  • Alternative Method for Deriving Stem Cells Proven in Mice
    A technique called "Altered Nuclear Transfer" (ANT) proposes to create patient-specific stem cells without destroying an embryo. In traditional nuclear transfer, patient-specific stem cells are created by removing the nucleus from a donated human egg and replacing it with the nucleus (usually from a skin cell) of a patient. Scientists stimulate the egg to divide, and destroy the embryo after 5 days to collect what will become human embryonic stem cells. ANT proposes that scientists turn off a gene needed for implantation in the uterus (Cdx2) in the patient cell nucleus before it is transferred into the donor egg. The proponents of ANT attempt to address concerns about embryo destruction by suggesting that because the entity created is unable to implant in the uterus, it is not a true embryo. NIH-supported scientists recently reported proof of principle tests that ANT works in mice. Mouse ANT entities whose Cdx2 gene is switched off are unable to implant in the uterus and do not survive to birth. However, scientists used ANT to create viable stem cell lines capable of producing almost all cell types. The authors point out that this technique must still be tested with monkey and human embryos, and the manipulation needed to control Cdx2 expression introduces another logistical hurdle that may complicate ANT's use to derive embryonic stem cells. (Nature 439(7073):212–5, laboratory of R. Jaenisch)
  • Human Stem Cells Help Rats with Spinal Cord Injury
    Transplanted stem cells have the potential to help repair or replace damaged nerve cells in individuals who have suffered a spinal cord injury. Before such treatments are attempted in humans, however, scientists must first establish stem cells' efficacy in animals. NIH-supported scientists injected human neural stem cells into the damaged spinal cords of rats. Four weeks after the injections, rats treated with human cells regained use of their back paws and were able to coordinate steps between their front and back paws. Spinal cord injured rats injected with either of two controls—culture media alone or human connective tissue cells—did not coordinate their steps and did not recover use of their rear paws. The scientists then selectively eliminated the human stem cells by injecting the rats with diphtheria toxin—which kills only human cells. Stem cell–injected rats that had recovered back paw use subsequently lost this ability, suggesting that the human stem cells were responsible for their improved mobility. Microscopic examination of the rats' spinal cords demonstrated that human stem cells had not only become nerve cells, but also formed working connections with the rat spinal cord nerve cells. Other human stem cells became supporting cells that covered parts of the injured spinal cord with a necessary sort of electrical insulation known as myelin. Although more tests must be done before this kind of stem cell therapy is ready for use in humans, these studies provide hope that human stem cells may one day restore mobility to individuals with spinal cord injuries. (Proceedings of the National Academy of Sciences of the USA 102:14069–14074, laboratory of A.J. Anderson)
  • Human Embryonic Stem Cells Can Reprogram Adult Human Cells
    Scientists are developing new ways to produce stem cells that will match an individual. Privately-funded scientists fused cultured adult human skin cells with human embryonic stem cells (hESCs). The resulting "hybrid" cells had many characteristics of hESCs—they grew and divided in a similar manner and manufactured proteins that are typically made in hESCs. Some as-yet unknown factor(s) within the hESCs enabled them to "reprogram" the adult skin cells to behave as hESCs. The cells still raise a significant technical barrier that must be overcome before they can be used to treat patients. Because fused cells are tetraploid (they contain four copies of the cellular DNA rather than the normal two copies), scientists must develop a method to remove the extra DNA without eliminating their hESC-like properties. If this hurdle can be overcome, this technique may one day allow scientists to create patient-specific stem cells without using human eggs. At present, this new approach to creating stem cells is a useful model system for studying how stem cells "reprogram" adult cells to have properties of pluripotent cells. (Science 309:1369–1373, laboratory of K. Eggan)
  • Are There Changes in Human Embryonic Stem Cells after Long Periods in Culture? One unique characteristic of human embryonic stem cells (hESCs) is their ability to remain unchanged even after long periods in culture. Scientists know that cells grown in laboratory culture for a long time have the tendency to develop changes in their DNA and that even hESCs will eventually develop such changes. They are using sensitive techniques to monitor hESC DNA. Two groups of scientists have recently reported their results using different techniques to analyze the DNA of hESCs on the NIH Human Embryonic Stem Cell Registry.

    One group examined the expression of specific genes regulated by a process known as imprinting. In imprinting, one of the two copies of a gene inherited from the parents is normally turned off, or inactivated, by the addition of a chemical group known as a methyl (CH3). When a gene is inactivated by adding CH3, the process is known as methylation. Although the group identified some disruptions in normal methylation after a long period in cell culture, they concluded that overall methylation patterns in these cells are remarkably stable. They predict that the changes would not prevent earlier passages of these cells from being used for cell-based therapies. (Nature Genetics 37:585–587, laboratory of R. Pedersen)

    The second group compared gene expression in early and late passages of the hESC lines. In later passages, they discovered changes in regions of the DNA that are frequently changed in human cancers. Their analyses suggest that these changes are significant and predict differences in how fast the cells grow and divide and in what types of tissues they may be capable of generating. (Nature Genetics 37(10):1099–103, multilab group, NIH-funded.)

    These studies suggest that the hESCs on the NIH Registry accumulate DNA and methylation changes after extended time in culture. These changes argue for the use of early-passage cells for developing cellular therapies to treat human beings.

  • Human Embryonic Stem Cell Derivatives Help Spinal-Cord-Injured Rats Regain Mobility
    Individuals who suffer spinal cord injuries (SCI) lose not only the nerve cells in the spinal cord, but also the supporting cells that insulate nerve cells with a fatty membrane called myelin. Loss of myelin plays an important role in loss of mobility in individuals with SCI. Privately funded researchers directed human embryonic stem cells to become early oligodendrocytes—the cells that form the myelin sheath around nerve cells. Next, they injected purified batches of these cells into the spinal cords of rats at either 7 days or 10 months after they suffered a blow to their spinal cords. Although some cells survived and developed into oligodendrocytes in both groups, only the rats injected at 7 days following injury regained myelin and demonstrated improved mobility after treatment. This result suggests that there is a critical period of time immediately following SCI for treatment using stem cell derivatives. If this work can be repeated in human beings, individuals with SCI who are treated soon after injury may be able to regain lost mobility. (The Journal of Neuroscience 25:4694–4705, laboratory of H.S. Keirstead)
  • Improved Method for Determining Gene Function in Human Embryonic Stem Cells
    In January 2004, scientists supported by the United Kingdom reported using RNA interference (RNAi) to decrease expression of a targeted hESC gene (see New Methods to Determine Gene Function in Human Embryonic Stem Cells). Now, NIH-funded scientists have improved the use of RNAi to determine the function of genes normally expressed in hESCs. The improved method "blocks" enough of the targeted gene's activity that it approximates gene knockout. In contrast to gene knockout, however, RNAi requires much less time and effort to achieve similar results. This improved technique gives researchers a powerful tool for determining what a gene does in order to maintain a stem cell's essential properties, such as the ability to produce more of itself (self-renewal) and to keep itself in a primitive state that can develop into any cell type in the body (pluripotent). (Stem Cells 23:299–305, laboratory of G.Q. Daley)
  • Same Embryo as Source of Stem Cells and Feeder Layers
    Scientists supported by the United Kingdom have developed a new method for supporting human embryonic stem cells (hESCs) in culture. The method, known as an autogenic feeder system, eliminates the potential for contamination from animal feeder cells or from human feeder cells derived from another donor. The scientists allowed some hESCs to differentiate into fibroblast-like cells, which they call human embryonic stem cell differentiated fibroblasts (hES-dFs). They used the hES-dFs as a feeder layer to support hESCs from their own parent line. HESCs cultured using this autogenic system remained pluripotent and undifferentiated. (Stem Cells 23:306–314, laboratory of M. Stojkovic)
  • Newborn Babies' Hearts Contain Multipotent Stem Cells
    NIH-supported scientists have identified multipotent stem cells within the hearts of newborn rats, mice, and human beings. These rare cells express a gene that identifies them as remnants of a cell population that forms part of the heart muscle during development. When grown in culture, the heart stem cells could be coaxed to produce both heart muscle cells and more stem cells. The heart cells produced demonstrated essential features of heart muscle: They made heart muscle proteins, conducted electrical current, and beat in rhythm with other heart muscle cells in the culture dish. If scientists can improve the technique to isolate and grow more of these stem cells, they may one day be able to use them for repairing hearts damaged by disease or injury. (Nature 433:647–653, laboratory of K. Chien)
  • Embryonic Stem Cells Cure Mouse Model of Hemophilia
    Hemophilia is a rare inherited disorder in which the blood does not clot normally. The disease is caused when the liver does not produce any (or insufficient amounts of) blood clotting factors. Individuals with hemophilia can be treated with infusions of blood clotting factors, but these only help for a short time. Scientists are searching for ways to permanently restore these individuals' blood-clotting ability. NIH-supported scientists used stem cells to cure mice suffering from a disorder similar to human Hemophilia B. The scientists incubated mouse embryonic stem cells for 7 days with a growth factor called FGF, for Fibroblast Growth Factor. After this treatment, the cells' protein-producing machinery stopped making templates for embryonic proteins and began making templates for proteins of early digestive system cells. When injected into the livers of "hemophilic" mice, the cells survived and made the missing blood-clotting factors. If these results can be repeated in human beings, doctors may one day be able to use human embryonic stem cells (hESCs) to restore blood clotting abilities to individuals with hemophilia. (Proceedings of the National Academy of Sciences of the USA 102:2958–2963, laboratories of O. Smithies and J. Frelinger)
  • Pax3 Serves as Switch for Stem Cells
    Stem cells have the unique ability to make more of themselves (self-renewal) and to make cells that go on to replace damaged or worn out cells in the body. Scientists are actively searching for the key genes that control the switch from remaining a stem cell to becoming differentiated cell types, such as nerve cells, heart muscle cells, or insulin-producing cells. By studying adult stem cells in hair follicles, NIH-funded scientists have identified a gene that helps regulate stem cell fate. The gene, known as Pax3, simultaneously gets stem cells ready to differentiate yet blocks them from doing so. If the cells are ever to differentiate, a protein called β-catenin must first free them from their developmental arrest. This study identifies another link in the chain of events that controls stem cell fate. A basic understanding of these events may enable scientists to identify and use stem cells to treat injury and disease in humans. (Nature 433:884–887, laboratory of J. Epstein)
  • Young Blood Rejuvenates Stem Cells in Aged Muscles
    Damaged skeletal muscles repair themselves by recruiting muscle stem cells called satellite cells to develop into new muscle fibers. Similar to other cellular processes of the body, muscle repair becomes less efficient with age. Scientists are searching for ways to restore regenerative capabilities to older human beings. NIH-supported scientists compared muscle injury repair in mice whose circulatory systems were joined in a process called parabiosis. They examined pairs of young-young, young-old, and old-old mice where one mouse in each pair received a muscle injury. As expected, muscles in the young pair regenerated quickly, while those in the old pair did not. However, an injured muscle in an old mouse paired with a young mouse was repaired as quickly as in young mice. The scientists determined that the new muscle fibers in the old mouse originated from satellite cells within the old mouse. Thus, something in the blood of the young mouse rejuvenated the satellite cells in the old mouse. The research group is now trying to determine what factor is responsible for the rejuvenation. This work in mice may one day enable doctors to stimulate muscle repair in older human beings. (Nature 433:760–764, laboratory of T. Rando)
  • Human Marrow-Derived Cells Help Repair Heart Attack Damage
    Although scientists have previously described multipotent human bone marrow cells, they typically studied mixed cellular populations. NIH-supported scientists have now been able to isolate and study single cells from human bone marrow that have characteristics of multipotent stem cells. These single cells are able to multiply, develop into many different cell types, and self-renew. The human cells seem to have the ability to repair rat heart muscle damaged by a heart attack when they are injected into the damaged region. Hearts of treated rats demonstrated better pumping ability than those of untreated rats. Some of the injected cells fused with, preserved, and stimulated division of existing heart muscle cells, while others appeared to differentiate into new heart muscle cells. The scientists also noticed increased blood vessel growth in the damaged area following treatment with the bone marrow stem cells. If this work can be repeated in humans, it offers the hope of treatment for those who suffer a heart attack. See also Stem Cell Therapy for the Heart: Hope and Controversy. (Journal of Clinical Investigation 115:326–338, laboratory of D. Losordo)
  • Developing Defined Medium for Cultured Human Embryonic Stem Cells
    Scientists are working to develop a "defined medium"—containing only known components—for growing human embryonic stem cells (hESCs). Their goal is to replace animal-derived feeder layers and serum with the defined medium. NIH-supported scientists combined basic fibroblast growth factor (bFGF) with noggin, a factor that blocks the action of a differentiation-inducing molecule called bone morphogenetic protein (BMP4). This bFGF/noggin combination helped keep hESCs in an undifferentiated state even when the cells were grown without feeder layers and animal-cell conditioned medium. Because this method uses media containing some animal products, it is still not a completely defined medium. However, this discovery brings us one step closer to developing a true defined medium for hESC culture. (Nature Methods 2:185–190, laboratory of J. Thomson)
  • Derivatives of Human Embryonic Stem Cells Insulate Spinal Cord in Mouse Mutant
    The nervous system sends nerve impulses (signals) through chains of interconnected neurons, or nerve cells. The parts of the neurons that send impulses, called axons, are insulated by sheaths of fatty membranes known as myelin. Similar to plastic coating on electrical wires, myelin sheaths prevent leaking of the electrical signal and help neurons conduct their impulses at a faster rate. In the human central nervous system (CNS), the myelin coating is formed when cells called oligodendrocytes wrap their membranes around the axons of neighboring neurons. Individuals whose myelin sheaths are damaged may have problems with movement and/or detecting sensory input. Many diseases of the human nervous system are caused by damage to myelin. Scientists are working to develop methods to replace myelin damaged by injury or disease. Privately funded scientists have now developed a way to direct human embryonic stem cells to become oligodendrocytes. When transplanted into the spinal cords of mice mutants lacking CNS myelin, the human oligodendrocytes wrapped around the bare axons and made them appear similar to axons in normal mice. The next step will be to determine if the human myelin restores normal nervous system function in these mutant mice. If this work can be repeated in humans, it may enable scientists to help individuals with nervous system disorders recover some of their mobility and sensations. (Glia 49:385–396, laboratory of H.S. Keirstead)
  • Scientists Generate Motor Neurons from Human Embryonic Stem Cells
    Individuals who suffer spinal cord injury or motor neuron diseases such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) do not currently have any treatment options that actually reverse their conditions. Available medical therapies treat only specific symptoms. Scientists are working to generate motor neurons from human embryonic stem cells (hESCs) in the hope of enabling these individuals to move and function once again. NIH-supported scientists have identified crucial steps in human nervous system development that allowed them to drive hESCs into cells that express markers and transmit nerve impulses in a manner similar to motor neurons. They discovered critical differences in how motor neurons develop in mice versus how they develop from human cells in vitro. Motor neurons generated in this manner may be useful for screening potential drugs to treat disorders such as ALS. If they are able to function in human beings after transplantation, these cells may also serve as a renewable source of replacement motor neurons to treat spinal cord injury and motor neuron diseases. (Nature Biotechnology 23:215–221, laboratory of S-C. Zhang)
  • Transplanted Cells Improve Symptoms in a Monkey Model of Parkinson's Disease
    Parkinson's disease occurs when an individual loses a large number of nerve cells, or neurons, that make an important brain chemical called dopamine. Without enough dopamine, neurons in the brain's movement coordination center fire out of control, and individuals with the disease are unable to control their movements. Scientists hope to treat Parkinson's disease by replacing the dopamine-producing neurons. Recently, scientists supported by the Japanese government developed an efficient method for generating dopamine-producing neurons from monkey embryonic stem cells. When transplanted into a monkey model of Parkinson's disease, a small number of the cells survived (1–3%), and disease symptoms seemed to improve. Future studies will need to determine whether transplanted cells could survive for longer time periods and whether they might pose a risk of forming tumors. This work provides further evidence that embryonic stem cells may one day be useful for treating neurological diseases in human beings. (Journal of Clinical Investigation 115:102–109, laboratory of N. Hashimoto)
  • New Human Embryonic Stem Cell Lines Developed as Models for Genetic Disorders
    Privately funded scientists have derived human embryonic stem cell (hESC) lines from embryos that carry genetic diseases. The abnormal embryos were identified during preimplantation genetic diagnosis (PGD), a test used to avoid transferring diseased embryos into the uterus of a woman undergoing in vitro fertilization. The new stem cell lines can now be used to help scientists understand how things go wrong in diseases such as thalessemia, Fanconi's anemia, muscular dystrophy, Huntington's disease, Marfan syndrome, adrenoleukodystrophy, and neurofibromatosis. (Reproductive Biomedicine Online 10:105–110, Reproductive Genetics Institute)
  • Human Embryonic Stem Cells Express Non-Human Sugar Molecule
    Many human beings have antibodies against the non-human sugar molecule called N-glycolylneuraminic acid (Neu5Gc) circulating in their blood. Scientists hypothesize that the antibodies are produced after a person is exposed to Neu5Gc in animal products consumed as food. NIH-supported scientists have now determined that human embryonic stem cells (hESCs) grown on mouse feeder cells and supported with animal-derived cell culture products express Neu5Gc on their cell surfaces. Cultured hESCs exposed to human blood serum were marked for destruction by the immune system. However, scientists do not yet know whether transplanted cells derived from these hESCs (such as insulin-producing cells or dopamine-producing cells) would be destroyed by the immune system. This study identifies another safety concern that must be addressed before derivatives of hESCs could be used to treat patients in clinical trials. (Nature Medicine 11:228–232, laboratory of A. Varki)
  • Gray Hair Due to Failed Maintenance of Pigment Stem Cells
    Melanocytes are cells that produce the human hair and skin pigment melanin. Hair appears gray when it lacks melanin. A new study by NIH-supported scientists found that mouse mutants with prematurely gray fur lose melanocyte stem cells, presumably because the mutations interfere with their ability to maintain the stem cell population. When they examined normal human hair follicles, the scientists found that the number of melanocyte stem cells gradually decreases with age. Thus, although hair follicles from 20- to 30-year-old humans had large numbers of melanocyte stem cells, the follicles of 40- to 60-year-olds had fewer, and most follicles of 70- to 90-year-olds had few or no remaining melanocyte stem cells. These results provide new insight into the mechanisms behind stem cell maintenance and may help us to understand how and why aging human beings lose stem cells in other organ systems. (Science 307:720–724, laboratory of D. Fisher)
  • Self-Replicating Insulin-Producing Cells Generated from Adult Pancreas
    Transplantation of insulin-producing beta islet cells offers a promising therapy to treat diabetes. Since there is a limited supply of islet cells available for transplantation, scientists are looking for stem cells that can be induced to produce insulin and treat diabetes. NIH intramural scientists developed a cell culture procedure that can drive epithelial cells in human islets to a mesenchymal (primitive) cell type. Although the mesenchymal cells do not produce insulin, they are capable of multiplying 1012-fold, thus providing a large supply of pancreatic stem cells. After the scientists once again change the culture conditions, these cells form islet-like clusters which produce 3 of the 4 islet hormones: insulin, glucagon, and somatostatin. In culture, these cells produced far less insulin than human pancreatic islet cells. However, after being transplanted into nondiabetic mice, they produced human insulin at levels previously shown to correct blood sugar in diabetic mice. If scientists succeed at getting these cells to secrete enough insulin to regulate blood sugar in human beings, they may one day be useful for treating diabetes. (Science 306:2261–2264, laboratory of M. Gershengorn)

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