Progress in understanding reprogramming to the induced pluripotent state

Abstract

This Review summarizes the progress to date on efforts to understand the molecular mechanisms underlying transcription factor-induced reprogramming of somatic cells to a pluripotent state (known as the induced pluripotent stem cell (iPSC) state). We discuss potential causes for the inefficiency of the reprogramming process and highlight epigenetic barriers that cannot be easily overcome by the reprogramming factors. New technologies and experiments are helping to determine the chronology of steps leading from loss of the somatic state to gain of pluripotency. We are gaining mechanistic insights into the role of each of the reprogramming factors during the progression to pluripotency. This Review also highlights the role of repressive chromatin as an inhibitor of reprogramming and discusses how chromatin states change at various stages of the process. Studies of X chromosome inactivation and reactivation underscore the degree of chromatin remodelling that occurs during reprogramming. Failure to reactivate the somatically silent X chromosome in female human iPSCs is suggestive of differences in the developmental state between human and mouse embryonic stem cells (ESCs) and iPSCs. Molecular comparisons of ESCs and iPSCs have uncovered various differences between these cell types, and some are informative about the mechanisms underlying the reprogramming process. Finally, we speculate that a combination of novel technologies will accurately define all the molecular events of reprogramming.