Easier way to make stem cells

Harvard researchers use chemicals in place of two cancer genes in reprogramming process

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CAMBRIDGE, Mass.—Harvard Stem Cell Institute researchers have successfully used chemicals to make stem cells, a finding which could lead to the use of chemicals to reprogram cells instead of genes and viruses, according to a recent study.

The study, published Oct. 12 in the Nature Publishing Group journal Nature Biotechnology, presents the possibility of reprogramming cells through purely chemical means, "which would make therapeutic use of reprogrammed cells safer and more practical."

Eliminating the use of genes—and the viruses used to insert them into target cells—is a goal of scientists doing reprogramming work, because the genes become integrated into the genome of the target cells and may change them in ways not yet understood or anticipated.
Using valproic acid, a chemical often used as a medication to treat seizure disorders, the scientists loosened the chromatin—the packaging of the cellular chromosome—making it easier to alter the cell's DNA to transform ordinary human skin cells into more powerful induced pluripotent cells.

The researchers used retroviruses to carry two of the four genes routinely used in reprogramming experiments. Because the two genes—c-Myc and Klf4—are cancer genes, this method of creating stem cells could be used to treat the disease, says Dr. Danwei Huangfu, lead author of the study. Previously, Huangfu used a chemical to improve the efficiency of the gene-induced reprogramming process in mice cells.

The study's findings have other far-reaching implications. For example, this method could be used to regenerate the pancreatic cells destroyed in type 1 diabetes and perhaps cure that disease, according to the researchers.

The researchers will now probe whether chemicals can replace all of the genes used in reprogramming, because genes instruct the cell to reprogram itself back to a stem cell state.

"We may need two types of chemicals, one to loosen the chromatin structure, and another to activate a genetic program for the stem cell state," Huangfu says. "We are looking for that reprogramming chemical, and it should be possible to find."

The study, Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2, was co-authored by a group of researchers from the Harvard Stem Cell Institute, the Japan Science and Technology Agency's ICORP Organ Regeneration Project, the Whitehead Institute for Biomedical Research and the Biomedical Sciences department of Utrecht University in the Netherlands.


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