“Latest Stem Cells News”

Neuron transplants have repaired brain circuitry and substantially normalized function in mice with a brain disorder, an advance indicating that key areas of the mammalian brain are more reparable than was widely believed.

Collaborators from Harvard University, Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) transplanted normally functioning embryonic neurons at a carefully selected stage of their development into the hypothalamus of mice unable to respond to leptin, a hormone that regulates metabolism and controls body weight. These mutant mice usually become morbidly obese, but the neuron transplants repaired defective brain circuits, enabling them to respond to leptin and thus experience substantially less weight gain.

Repair at the cellular-level of the hypothalamus — a critical and complex region of the brain that regulates phenomena such as hunger, metabolism, body temperature, and basic behaviors such as sex and aggression — indicates the possibility of new therapeutic approaches to even higher-level conditions such as spinal cord injury, autism, epilepsy, ALS  (Lou Gehrig’s disease), Parkinson’s disease, and Huntington’s disease.

“There are only two areas of the brain that are known to normally undergo ongoing large-scale neuronal replacement during adulthood on a cellular level — so-called ‘neurogenesis,’ or the birth of new neurons — the olfactory bulb and the subregion of the hippocampus called the dentate gyrus, with emerging evidence of lower level ongoing neurogenesis in the hypothalamus,” said Jeffrey Macklis, Harvard University professor of stem cell and regenerative biology and HMS professor of neurology at MGH, and one of three corresponding authors on the paper. “The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling.  Here we’ve rewired a high-level system of brain circuitry that does not naturally experience neurogenesis, and this restored substantially normal function.”

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The same genes that are chemically altered during normal cell differentiation, as well as when normal cells become cancer cells, are also changed in stem cells that scientists derive from adult cells, according to new research from Johns Hopkins and Harvard.

Although genetically identical to the mature body cells from which they are derived, induced pluripotent stem cells (iPSCs) are notably special in their ability to self-renew and differentiate into all kinds of cells. And now scientists have detected a remarkable if subtle molecular disparity between the two: They have distinct “epigenetic” signatures; that is, they differ in what gets copied when the cell divides, even though these differences aren’t part of the DNA sequence.

“Relatively little study has been done on the epigenetic nature of stem cells,” says Andrew Feinberg, M.D., M.P.H., a professor of medicine at the Johns Hopkins University School of Medicine. “To date, the bulk of what is known about stem cells is focused on how you create them and grow them and so forth, but not on the essence of them, and what is fundamentally different about these cells.”

To compare and contrast mature connective tissue cells called fibroblasts with the pluripotent stem cells into which they were reprogrammed, the investigators focused on a chemical change known as methylation. This chemical change which, associated with silencing genes, is classified as epigenetic because, although not part of the DNA sequence, is copied when a cell divides. They identified and then measured so-called differentially methylated regions (DMRs) of genes whose expression was changed in the process of being reprogrammed from a parent cell to a stem cell.

Building on previous research that looked at where differently methylated sites were located in cancer cells, as well as on research that had shown these same sites matching up with many of the methylated areas that had been implicated in the differentiation of normal brain, liver and spleen tissues, the team discovered that the reprogramming of a cell to become a stem cell apparently involves many of the very same DMRs and genes.

“The surprise,” says Feinberg, “is that there is such a degree of overlap between the differently methylated regions and genes that are involved in turning a fibroblast into a stem cell and turning a normal cell into a cancer cell.”

The study, done jointly with George Q. Daley, M.D., Ph.D., and colleagues from Harvard University, was published Nov. 1 in the advanced online edition of Nature Genetics. The researchers suggest in the study that certain sites throughout the genome appear to be generally involved in distinguishing DNA methylation among different cell types and cancers, and these same sites are involved in reprogramming fibroblasts back into stem cells (…)

from http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20091104.074444&time=09%2059%20PST&year=2009&public=0

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An ‘antenna’ molecule, which is capable of guiding blood stem cells to their natural ‘home’, the bone marrow, has been discovered. The discovery could improve the efficiency of umbilical cord stem cell transplants. This type of transplant is not efficient when there are not many umbilical cord stem cells present, since few of them are able to reach the bone marrow from the blood.
Reported by Nature magazine, the discovery was made by David Scadden of the Harvard Stem Cell Institute in Boston. The stem cells, which normally renew the population of blood cells in the body (red and white blood cells and platelets), are found in the bone marrow, but continuously move throughout blood in circulation, and eventually end up back in the bone marrow.

This is the reason why blood stem cells transplants are never highly efficient. In fact, the injected stem cells are not always able to make it back to the bone marrow, where they need to be present in order to function. These researchers have discovered a guide molecule, a protein called ‘GSA’, which is like an antenna placed on the surface of the cells, which guides them back to the marrow. Researchers have demonstrated in mice that have received stem cell transplants, that with drugs that activate GSA, the injected stem cells easily find their way to the bone marrow and the transplant functions more efficiently.

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Five years after Harvard researchers first received institutional permission to attempt to produce stem cell lines via somatic cell nuclear transfer (SCNT), a young scientist who worked in the Harvard program as a postdoctoral fellow has succeeded in using the process — known as therapeutic cloning — to produce a stem cell line containing the genes of a patient with type 1 diabetes.

In papers in Nature, Nature Communications, and Cell Stem Cell, that scientist, who is now at the independent New York Stem Cell Foundation (NYSCF) laboratory, and Harvard researchers, report on the SCNT advance. In addition, they report on an experiment explaining why other attempts at SCNT have been unsuccessful and offer a commentary reporting that it is impractical, if not impossible, to recruit ova donors without paying them.

Ironically, all three reports serve to underscore how astoundingly fast the field of stem cell science has advanced since 2006, when it looked as though SCNT provided the only path to the creation of disease-specific stem cell lines from patients. These stem cell lines might then be used for studying disease development, for transplanting to treat diseases, and as targets for the development of conventional drugs.

The creation of induced pluripotent stem cells (iPS) and the successful reprogramming of one form of adult cell into another form of adult cell have provided researchers with alternatives to SCNT, and decreased interest in it. However, because it is still too early to know which avenue of research will prove the most useful in increasing understanding of various diseases, groups have continued their research efforts in SCNT as well.

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Douglas A. Melton

Scientists have created stem cells from patients suffering from 10 incurable diseases, from Down syndrome to diabetes and Parkinson’s – immortal cells that might one day be turned into repair material for wasting muscles or damaged brains.
The Harvard University-led team has taken skin and bone marrow cells from diseased patients and re-programmed those cells to behave like cells from days-old embryos.

The feat allows scientists for the first time to watch muscular dystrophy and other diseases unfold in a petri dish, “that is, to watch what goes right or wrong,” said Doug Melton, co-director of the Harvard Stem Cell Institute. The cells will also allow researchers to screen new drugs to treat the diseases.
“In these complex genetic diseases, we’re so ignorant at the moment we don’t even know when a patient gets diabetes if they all get it the same way,” Melton said. “There could be 50 different ways to get Type 1 diabetes.” The stem cell lines could help researchers hone in on exactly which mutations are responsible and find “the weak point where you could try to prevent, or treat it.”
“We have good reason to believe that this will make it possible to find new treatments, and eventually drugs, to slow or even stop the course of a number of diseases,” Melton said.
The new cells are “pluripotent” cells that can be coaxed into making any tissue in the human body, and can grow forever.

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A team of Harvard stem cell researchers has succeeded in reprogramming adult mouse skin cells directly into the type of motor neurons damaged in amyotrophic lateral sclerosis (ALS), best known as Lou Gehrig’s disease, and spinal muscular atrophy (SMA). These new cells, which researchers are calling induced motor neurons (iMNs), can be used to study the development of the paralyzing diseases and to develop treatments for them.

Producing motor neurons this way is much less labor intensive than having to go through the process of creating induced pluripotent stem cells (iPSC, iPS cells), and is so much faster than the iPS method that it potentially could reduce by a year the time it eventually takes to produce treatments for ALS and SMA, said Kevin Eggan, leader of the Harvard team.

Importantly, the direct reprograming does not involve the use of any factors known to trigger cancer or any other disease states, and the factors in fact make the fibroblasts, the connective tissue cells that make and secrete collagen proteins, stop dividing.

The work by Eggan, a member of the Harvard Stem Cell Institute principal faculty and an associate professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), and his colleagues builds on and advances work by SCRB co-chair and Professor Doug Melton, who pioneered direct cellular reprogramming, and Marius Wernig of Stanford, who used direct reprogramming to produce generalized neurons.

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