Salk and UCSD Scientists Identify Core Epigenetic Signature In iPSCs

Scientists from the Salk Institute at the University of California, San Diego have managed to characterize a unique molecular feature of induced pluripotent stem cells (iPSCs) that seems to earmark them. This earmark is a kind of signature of iPSCs, and it identifies them as reprogrammed cells. iPSCs show a great deal of promise in regenerative medicine because of their ability to differentiate into a wide range of body tissues, although there are safety concerns with these cells.

The Salk scientists report that there is a consistent molecular difference between embryonic stem cells and iPSCs. These findings could potentially help overcome some of the safety problems that must be solved if iPSCs are to be used in regenerative medicine.

Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and the senior author on the paper: “We believe that iPSCs hold a great potential for the treatment of human patients. Yet we must thoroughly understand the molecular mechanisms governing their safety profile in order to be confident of their function in the human body. With the discovery of these small, yet apparent, epigenetic differences, we believe that we are now one step closer to that goal.”

Embryonic stem cells (ESCs) possess a characteristic known as “pluripotency.” Pluripotency refers to the ability of these cells to differentiate into nearly any cell type in the adult human body. The pluripotency of ESCs makes them a candidate for therapeutic uses, but once ESCs differentiate into mature into specific cell types and then transplanted into a patient, they may elicit immune responses, potentially causing the patient to reject the cells.

To overcome this problem, scientists in Japan and the United States found ways to use genetic engineering techniques to revert mature, adult cells, into a pluripotent state. Thus were born “induced pluripotent stem cells” (iPSCs), which could be developed from the patient’s own adult cells, and would theoretically carry no risk of immune rejection.

Soon after iPSCs were discovered, however, scientists found that iPSCs had molecular differences from embryonic stem cells. In particular, iPSCs had “epigenetic changes.” Epigenetic changes are changes in those chemical modifications in DNA that can alter genetic activity. At certain points in the genomes of iPSCs, there are different patterns of methyl groups attached to the bases of DNA in comparison to the genomes of ESCs. At first, it seemed that these epigenetic changes occurred randomly.

Izpisua Belmonte and his colleagues worked on iPSCs in order to understand more about these differences. Were these epigenetic changes really random, or was there a discernible pattern?

Previous studies had primarily analyzed iPSCs derived from only one mature type of cells; a connective tissue cell called a fibroblast. However, the Salk and UCSD researchers examined 17 iPSC lines derived from six different mature cell types in order to determine if there were any commonalities. Their experiments revealed that even though there were hundreds of unpredictable changes, there were some epigenetic changes that were consistent across the cell types: the same nine genes were associated with these common changes in all iPSCs.

“We knew there were differences between iPSCs and ESCs,” said Sergio Ruiz, first author of the paper, “We now have an identifying mark for what they are.”

The therapeutic significance of these nine genes awaits further investigation, but the current importance of this study is that it gives stem cell researchers a new and more precise understanding of iPSCs, and their epigenetic signatures.

See: “Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells;” Sergio Ruiz et al.; Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1202352109