Harvard researchers use chemical to transform human skin cells into pluripotent cells


by Amy Swinderman

CAMBRIDGE, Mass.—Researchers at the Harvard Stem Cell Institute have successfully used valproic acid to transform human skin cells into pluripotent 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 through purely chemical means, “which would make therapeutic use of reprogrammed cells safer and more practical.” Eliminating the use of genes—and the viruses being 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, or iPS 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 Kenji Osafune, René Maehr, Wenjun Guo, Astrid Eijkelenboom, Shuibing Chen, Whitney Muhlestein and Douglas A. Melton, 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 in Cambridge, Mass.; and the Biomedical Sciences department of Utrecht University in the Netherlands. DDN

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