Mechanism of human somatic reprogramming to iPS cell

Somatic reprogramming to induced pluripotent stem cells (iPSC) was realized in the year 2006 in mice, and in 2007 in humans, by transiently forced expression of a combination of exogenous transcription factors. Human and mouse iPSCs are distinctly reprogrammed into a 'primed' and a 'naïve' state, respectively. In the last decade, puzzle pieces of somatic reprogramming have been collected with difficulty. Collectively, dissecting reprogramming events and identification of the hallmark of sequentially activated/silenced genes have revealed mouse somatic reprogramming in fragments, but there is a long way to go toward understanding the molecular mechanisms of human somatic reprogramming, even with developing technologies. Recently, an established human intermediately reprogrammed stem cell (iRSC) line, which has paused reprogramming at the endogenous OCT4-negative/exogenous transgene-positive pre-MET (mesenchymal-to-epithelial-transition) stage can resume reprogramming into endogenous OCT4-positive iPSCs only by change of culture conditions. Genome-editing-mediated visualization of endogenous OCT4 activity with GFP in living iRSCs demonstrates the timing of OCT4 activation and entry to MET in the reprogramming toward iPSCs. Applications of genome-editing technology to pluripotent stem cells will reshape our approaches for exploring molecular mechanisms.