|Stanford University School of Medicine scientists have demonstrated, in a study conducted jointly with researchers at Yale University, that induced-pluripotent stem cells are not as genetically unstable as was thought. For research using iPS cells to study disease and developing regenerative medicine this is welcome news.|
The new study, which will be published in Nature, showed that what seemed to be changes in iPS cells' genetic makeup — presumed to be inflicted either in the course of their generation from adult cells or during their propagation and maintenance in laboratory culture dishes — instead are often accurate reflections of existing but previously undetected genetic variations among the cells comprising our bodies.
For researchers hoping to use the cells to study disease or, someday, for regenerative medicine this is excellent news. But it raises the question of whether and to what extent we humans are really walking mosaics whose constituent cells differ genetically from one to the next in possibly significant respects, said Alexander Urban, PhD, assistant professor of psychiatry and behavioral sciences. Urban shared senior authorship of the study with bioinformatics professor Mark Gerstein, PhD, and neurobiology professor Flora Vaccarino, MD, both of Yale.
It's only a few years ago that human iPS cells started becoming available to researchers. These cells hold great promise because they act almost exactly like embryonic stem cells, which can be nudged to differentiate into virtually any of the body's roughly 200 different cell types. But iPS cells can be derived easily from a person's skin, alleviating numerous ethical concerns arising from the necessity of obtaining embryonic stem cells from fertilized eggs.
At least in principle, iPS cells' genetic makeup closely reflects that of the individual from whom they were derived. Today, "heart cells" derived from a heart patient's skin can be produced in a laboratory dish so scientists can learn more about that particular patient's condition and to screen drugs that might treat it. Tomorrow, perhaps, such cells could be administered to that patient to restore heart health without being perceived as foreign tissue by the patient's immune system, which would otherwise reject the implanted cells.
However, Urban said, several previous studies have raised worries regarding iPS cells' genomic stability. Whether it was the reprogramming procedure researchers use to convert ordinary adult cells into iPS cells or the culturing techniques employed to keep them alive and thriving afterward, something appeared to be inducing an upswing in these cells' manifestation of copy number variations, or CNVs — the disappearance or duplication of chunks of genetic material at specific locations along the vast stretches of DNA that coil to form the chromosomes residing in all human cells.
"This is a huge amount of cell-to-cell genetic variation," said Urban, who also participated in a recent study of human tissues conducted by the laboratory of Michael Snyder, PhD, professor and chair of genetics at Stanford. That study showed there can be distinct CNV patterns in kidney, pancreas and liver. "Rather than monoliths, our bodies may be mosaics composed of cells whose genomes differ. What we do not know is whether or when these differences are dangerous, irrelevant or beneficial."
That may depend on the organ, said Urban. "The more complicated something is, the more ways there are that something could go wrong with it. The brain is a particularly complicated organ. CNVs affecting cells in particular brain structures or areas could be playing a role in complex neurodevelopmental disorders such as schizophrenia and autism." Urban intends to find out, he said.
SOURCE Stanford University School of Medicine
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