Dissecting a mechanism for induced

By forcing the expression of certain genes, researchers can prompt non-reproductive cells to transform into early embryonic cells capable of giving rise to various cell types, a phenomenon known as induced pluripotency. Koji Tanabe et al. (pp. 12172–12179) circumvented the inefficiency of this process by revealing how the forced expression of four genes—OCT3/4, SOX2, KLF4, and c-MYC (OSKM)—can reliably induce pluripotency in reprogrammed fibroblasts derived from the connective tissues of human skin. The authors reveal critical time periods during which cells can initiate reprogramming and those expressing the OSKM transgene can commit to becoming pluripotent. Within one week of forcing OSKM expression in human fibroblasts, 1 in 5 cells began to display the TRA-1-60 antigen, a marker of pluripotency. When these cells were transferred to new plates, however, only 1 in 100 matured into induced pluripotent stem cells (iPSCs), whereas the remaining cells reverted to their original state. The authors explored four factors previously reported to promote reprogramming and found that the reversion could be suppressed by the RNA-binding protein, LIN28. According to the authors, these findings suggest that the maturation of iPSCs, rather than the initiation of pluripotency, poses the greatest obstacle to the reprogramming of human fibroblasts. — A.G.