Highlights of Stem Cell Research
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Archived Articles
2008 Articles
- Safer Reprogramming of Human Cells
In 2007, scientists generated induced pluripotent stem cells, or iPSCs, from adult skin fibroblasts (see Human Skin Cells Reprogrammed). Two features of the original technique make it unlikely that these cells will be used to derive cells for human transplantation. First, the reprogramming factors include cancer-promoting genes. Second, the factors are carried into the adult cells using inactivated viruses that integrate at random into the host DNA, introducing the possibility that the virus will interrupt or otherwise damage a critical gene. Scientists have recently developed several new alternative iPSC production methods. The iPSCs produced in each new method appear to be very similar to iPSCs produced in the traditional method. Each new method has its own advantages and disadvantages as compared to the original method, and each provides insight into how scientists may be able to develop iPSCs that are safe for use in clinical trials.
Privately funded investigators at Harvard University added a potent chemical, valproic acid, to newborn human skin (fibroblast) cells in culture. This treatment unravels the DNA to permit access to genes, and the scientists then needed to add only two reprogramming factors to the cells, rather than the usual four factors needed in traditional iPS cell reprogramming. The two eliminated factors are the potent cancer-promoting genes c-Myc and Klf4. This technique uses newborn rather than adult cells, and still uses potentially harmful viruses to reprogram. However, by successfully eliminating the 2 cancer-promoting factors, scientists hope they may one day be able to use chemicals rather than viruses to reprogram human cells. Nature advance online publication, laboratory of D. Melton. 2008 Oct 12.
NIH-supported scientists at Harvard University developed a method that uses a different virus—an adenovirus—as a means of carrying the reprogramming factors into newborn mouse skin and adult mouse liver cells. The adenovirus has the advantage of not usually integrating into the DNA, and thus avoids the potential for interrupting or otherwise damaging a critical gene. The virus needs to be present for only a short time (several days) in order to accomplish reprogramming. However, the technique is very inefficient when compared to generating iPSCs with retroviruses, still uses cancer-promoting genes, and the adenovirus may still integrate into the host DNA at low frequencies. The scientists are now working to use adenoviruses to reprogram human cells. Science advance online publication, laboratory of K. Hochedlinger. 2008 Sep 25.
A third group reported success at generating iPSCs without using any viruses. Japanese researchers successfully reprogrammed mouse cells by using only "naked" DNA of the reprogramming factors—in a circular, or plasmid form. The scientists introduced the plasmids into mouse embryonic skin cells via transfection, and were able to generate iPSCs. This method has the advantage of avoiding any use of viruses, but still uses cancer-promoting genes to accomplish reprogramming. It is also much less efficient than the original reprogramming method, and begins with embryonic skin cells, which may be more amenable to reprogramming than adult skin cells. Science advance online publication, laboratory of S. Yamanaka. 2008 Oct 9.
- Pluripotent Stem Cells from Adult Human Testis
In 2006, 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; see Pluripotent Stem Cells Found in Adult Mouse Testicles). Now, another team of German scientists has succeeded in generating pluripotent stem cells from tissue biopsied from human testicles. They call the cells human adult GSCs, for germline stem cells. Human adult GSCs demonstrate many characteristics of pluripotent cells, including the ability to form teratomas and generate cells characteristic of all three germ layers. Scientists hope to learn more about development and differentiation by comparing these human adult GSCs with both human embryonic stem cells (hESCs)and induced pluripotent stem cells (iPSCs). Nature advance online publication, lab of T. Skutella. 2008 Oct. 8.
- Adult Human Skin Cells Reprogrammed into Insulin-Secreting Cells
Scientists are developing a variety of options that may one day enable replacement of the insulin-producing beta islet cells of the pancreas that are lost in individuals with type 1 diabetes. Previously, NIH-funded scientists reprogrammed differentiated pancreatic exocrine cells in adult mice into cells that closely resemble beta cells. (See Adult Pancreas Cells Directly Reprogrammed to Insulin-Secreting Beta Cells.) In that study, mouse cells were not taken all the way back to a primitive, or embryonic-like state, but were converted to another fate, in a process the scientists termed "direct reprogramming". Now, privately funded scientists report reprogramming human foreskin fibroblasts into induced pluripotent stem cells, or iPSCs. The iPSCs were then differentiated into islet-like clusters (ILCs) that secreted insulin when glucose was added to the cell cultures in the laboratory. The researchers are now working to develop iPSCs from individuals with diabetes, in the hope of one day producing patient-specific insulin producing cells. Although transplantation can restore insulin production, it does not address the autoimmune destruction of the individual’s own beta cells that initially results in type 1 diabetes and may recur, thereby destroying the newly transplanted cells. Scientists also hope that cells generated from individuals with type 1 diabetes will be useful for testing potential diabetes drugs and for understanding the underlying cause of the disease. Journal of Biological Chemistry, laboratory of Y. Zhang. 2008 Sep 9.
- Adult Pancreas Cells Directly Reprogrammed to Insulin-Secreting Beta Cells
The success of iPS cell reprogramming (see Scientists Reprogram Adult Mouse Skin Cells by Adding Defined Factors) led scientists to wonder if adult cells could be directly reprogrammed from one type to another, without the need to take them all the way back to a pluripotent stem cell. NIH-funded scientists now report successful direct reprogramming of adult exocrine cells from the pancreas into cells that resemble beta cells. Based on their knowledge of normal beta cell development, they were able to "re-start" expression of three critical beta cell genes in the differentiated adult exocrine pancreas cells. The reprogrammed cells are similar to beta cells in appearance, size, and shape; express genes characteristic of beta cells; and are able to partially restore blood sugar regulation in mice whose own beta cells have been chemically destroyed. This method for reprogramming adult cells may now be used as a model for directly reprogramming other adult cell types. Nature advance online publication, laboratory of D. Melton. 2008 Aug 27.
- Adult Stem Cell Lines Created for 10 Additional Human Diseases
One week after the report of induced pluripotent stem cells (iPS cells) generated from an Amyotrophic Lateral Sclerosis (ALS) patient, NIH-funded scientists reported generating iPS cell lines carrying 10 additional human diseases. The new iPS cell lines were generated from individuals with Duchenne muscular dystrophy, Becker muscular dystrophy, juvenile-onset (type 1) diabetes, Parkinson's disease, Huntington's disease, Down syndrome, ADA severe combined immunodeficiency, Shwachman-Bodian-Diamond syndrome, Gaucher disease, and a carrier of Lesch-Nyhan Syndrome. As before, scientists must still determine whether the relevant cell types derived from these lines demonstrate symptoms of the diseases. For example—do muscle cells from the Duchenne MD iPS line behave as they do in individuals with the disease? The cell lines are capable of long term self-renewal in culture, thus providing a potentially endless supply of material for study of disease processes and testing of potential drugs on human cells. Scientists may now be able to generate and compare iPS lines from individuals with the same disease but different symptoms—a potential insight into what is due to inheritance and what is due to environment. Cell advance online publication, laboratories of C. Cowan, K. Hochedlinger, G. Daley. 2008 August 6.
- Mouse Embryonic Stem Cells Used to Predict Human Breast Cancer Risk
Scientists at the National Cancer Institute (NCI) at the NIH report a research breakthrough in predicting human breast cancer risk. Nature Medicine 14(8), laboratory of S. Sharan. 2008 August 1.
- Scientists Generate Stem Cell Line from Patient with Lou Gehrig's Disease
Privately funded scientists report successfully generating stem cells from a patient with an inherited form of Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS). Starting with skin cells from the patient, the scientists used viruses to insert factors to reprogram the adult skin cells into induced pluripotent stem cells (iPSC) (see Human Skin Cells Reprogrammed). Once they had generated an ALS-iPSC line, the scientists coaxed the cells into becoming the type of motor neurons that are destroyed in ALS. These iPSC-derived motor neurons carry genes responsible for ALS and hold great potential for investigating the ALS disease process in human cells. Scientists are still uncertain whether the iPSC-derived motor neurons will degenerate in the same way as the patient's naturally occurring motor neurons. Ongoing experiments are comparing healthy motor neurons to the ALS-iPSC–derived motor neurons. If the iPSC-derived motor neurons show signs of ALS-like degeneration, they will be invaluable for observing events in the course of the ALS disease process and for testing potential ALS drugs on human cells in the laboratory before the drugs are used in humans. Science advance online publication, laboratory of K. Eggan. 2008 July 31.
- Adult Mouse Neural Stem Cells Reprogrammed Using Fewer Factors
The current techniques for reprogramming adult cells require the use of viruses to insert several pluripotency factors into each cell's DNA (see Human Skin Cells Reprogrammed). Both viruses and DNA insertions could cause negative health consequences, so elimination of one or both is desirable if reprogrammed cells are to be used in clinical applications. German scientists selected a starting cell type (adult neural stem cells) that already expresses high levels of two factors known to be important for reprogramming. Using these cells, the scientists generated reprogrammed adult cells by inserting fewer factors. If this technique works in other types of adult cells with high levels of endogenous reprogramming factor expression, it will bring the field one step closer to enabling the use of stem cells to treat humans. Nature 454:646–50, laboratory of H. Scholer. 2008 July 31.
- Transplanted Adult Stem Cells Improve Muscle Function in Mouse Model of Muscular Dystrophy
In January, privately funded scientists reported improvement in a mouse model of muscular dystrophy (MD) treated with muscle cells derived from mouse embryonic stem cells. Now, NIH-funded scientists have developed a method to isolate a specific type of adult mouse muscle stem cells that improves muscle function when transplanted into mice suffering from muscular dystrophy. The transplanted muscle stem cells were also able to establish a pool of non-diseased cells for continued repair and replacement of damaged muscle. This method uses mouse muscle stem cells, rather than beginning with undifferentiated embryonic stem cells and driving them to become muscle. Scientists hope to identify a similar human adult muscle stem cell population in order to learn more about what enables the cells to self-renew and possibly to learn to boost their regenerative potential. This research may one day lead to treatments for individuals with MD. Cell 134(1):37–47, laboratory of A. Wagers. 2008 July 11.
- Human Embryonic Stem Cells Generate Heart Progenitor Cells
Heart disease, or coronary artery disease, is a leading cause of death in the United States. Although treatments for heart disease are constantly improving, scientists would also like to be able to replace damaged heart tissue. One possible source is human heart cells derived from human embryonic stem cells (hESCs). Previously, scientists were able to drive mouse embryonic stem cells to become mouse cardiovascular progenitor cells, which have the capacity to become any of the three distinct cell types that compose the adult heart. Now the same scientists have induced hESCs to become human heart progenitor cells. As with the mouse heart progenitor cells, the human heart progenitor cells can produce the three main heart cell types—cardiomyocytes (contractile heart muscle cells), endothelial cells (cells that line the blood vessels), and vascular smooth muscle cells (cells that provide elasticity to blood vessels). The scientists identified key characteristics that enabled them to sort the heart progenitor cells from other cells in culture. Finally, they verified that cardiomyocytes derived via this process are functional by examining their expression of cardiac genes, their ability to conduct electrical current, and their ability to repair the pumping ability of mouse hearts damaged by induced heart attacks. This work provides a first step for developing human heart cells to be used for human heart tissue transplantation, or to test prospective heart drugs. Nature 453(7194):524–8, laboratory of G. Keller. 2008 May 22.
- Neurons from Reprogrammed Adult Mouse Skin Cells Improve Symptoms in Rat Model of Parkinson's Disease
Scientists hope one day to replace the dopamine-producing nerve cells (neurons) lost in Parkinson's Disease with neurons derived from stem cells. Previously, scientists coaxed human embryonic stem cells (hESCs) into becoming dopamine-producing neurons. Another team of scientists now report generating dopamine-producing neurons from mouse-induced pluripotent stem cells (iPSCs). They tested the function of their derived dopamine-producing neurons by injecting them into the brains of rats used as a model for Parkinson's disease. Treated rats showed improvement in their Parkinsonian symptoms. These results demonstrate that animal iPSCs are capable of replacing lost cells and improving disease in animal models. They also offer hope that human iPSCs may one day enable scientists to develop patient-specific cells for replacing those lost or damaged by disease. Proceedings of the National Academy of Sciences of the USA 105(15):5856–5861, laboratory of R. Jaenisch. 2008 April 15.
- What Molecular Changes Enable Reprogramming?
Scientists have successfully reprogrammed adult mouse and human cells to behave like embryonic stem cells (ESCs). These reprogrammed adult cells are known as induced pluripotent stem cells, or iPS cells. Although iPS cells share many characteristics of ESCs, scientists have not yet identified what molecular changes enable reprogramming. To address these questions, NIH-funded scientists developed a special virus that allowed them to start and stop the expression of genes used in reprogramming (Oct4, Sox2, c-Myc, and Klf4) at will. Using their new "on/off switch," they determined the minimum amount of time that an adult cell must be exposed to these gene products in order to be reprogrammed. They also identified specific events, such as changes in level of gene expression or gene activation versus inactivation, that are indicative of cells at different stages of the reprogramming process. Scientists can now use this information to sort cells that are reprogrammed from those that are not. They will also be able to use what they know about the stages of reprogramming and exposure time as they develop new reprogramming techniques that eliminate the potential cancer risks of the viruses and genes used in the current methods. Cell Stem Cell 2(3):230–240, laboratory of K. Hochedlinger. 2008 March 6.
- Human Embryonic Stem Cell-Derived Neurons Treat Stroke in Rats
Scientists hope to use embryonic stem cells to generate neurons to replace those lost to disease, including the loss of nerve cells (neurons) in the brain that happens after a stroke. Scientists can already drive human embryonic stem cells (hESCs) into becoming neurons. However, transplants of these cells into animal models of human diseases sometimes "overgrow" and form tumors, suggesting that the transplants contain both desirable neurons and undesirable undifferentiated cells. NIH-funded scientists now report developing a cell culturing method that selects only human neural stem cells (hNSCs), and then drives them to become mature neurons, with no undifferentiated cells remaining. Transplants of these cells into rats did not produce any tumors, at least within the 2 month period of observation. In addition, rats that had suffered a stroke and subsequently stopped using one front paw began using that paw again after receiving transplanted human neurons. Post-mortem tissue sections of the treated rats' brains showed transplanted human neurons grew towards the site of neuron loss and did not appear to generate any tumors. The scientists now hope to study these hESC-derived neurons to learn how they differentiate and how they are different from human neurons derived from other culturing methods or tissue sources. Scientists also hope to adapt this technique to treat human stroke patients. PLOS One 3(2): e1644, laboratory of G.K. Steinberg. 2008 February 20.
- Muscular Dystrophy in Mice Treated with Muscle from Mouse Embryonic Stem Cells
Muscular dystrophy (MD) is an inherited disease characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Current treatments for MD aim to slow the disease's progression but can't cure it or completely halt its progression. One possible hope lies in replacing diseased muscles with new muscle cells, generated from embryonic stem cells (ESCs). However, scientists have had difficulty generating skeletal muscle from ESCs, due in part to a lack of useful ways to identify developing skeletal muscle amidst other cell types. Privately funded scientists have now developed such a method in mice, as well as another method to sort muscle cells from undifferentiated stem cells that could divide uncontrollably and produce tumors after transplantation. The scientists injected the mouse ESC–derived skeletal muscle cells into mice with an MD-like muscle-wasting condition. Tests showed that treated mice's muscles had an improved ability to contract, and treated mice fared better than untreated diseased mice on standard tests for muscle function. In the future, scientists hope to test the ability of human embryonic stem cell (hESC)–derived muscle cells to treat human MD. Nature advance online publication, laboratory of R.C.R. Perlingeiro. 2008 Jan 20.
- Single Cell Biopsy Successfully Generates Human Embryonic Stem Cell Line; Biopsied Embryos Develop to Blastocyst Stage
In 2006, privately funded scientists successfully established human embryonic stem cell (hESC) lines using cells taken from pre-implantation human embryos (see Scientists Generate Human Embryonic Stem Cell Lines from Single Cells). However, the previous method involved dissociation of the embryos (i.e., the embryos were destroyed) and co-culture with existing hESCs. In this latest publication from the same laboratory, the scientists removed only one or two cells from each embryo via a biopsy procedure. These one or two cells were used to generate hESC lines. At the same time, the scientists cultured the biopsied embryos to the blastocyst stage and then froze them. One of the cell lines developed was cultured with a protein called laminin instead of being cultured with existing hESCs. 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. Cell Stem Cell doi:10.1016/j.stem.2007.12.013, laboratory of R. Lanza. 2008 Jan 10.
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