X-chromosome activity in naive human pluripotent stem cells—are we there yet?

A major goal for stem cell research and its clinical applications is to derive high quality human pluripotent stem cell (hPSC) lines that recapitulate in culture the properties of epiblast cells from human blastocyst embryos. Recent developments in derivation and culture conditions have allowed establishing so-called naive pluripotent hPSCs, which mimic closely the in vivo state on multiple levels like gene expression and differentiation potential. An epigenetic hallmark associated with naive pluripotency in female mouse cells is the reactivation of the X-chromosome and it was believed that this would be also the case for human naive cells. However, new evidence accumulates showing that the situation is not quite as simple. In this perspective, we describe the latest developments on this question and focus in particular on two recent studies by Sahakyan et al. and Vallot et al. (1,2), as they describe for the first time in detail the X-chromosome state of naive hPSCs. They provide important ground-work for studying human X-chromosome dynamics in vitro and for using the epigenetic X-chromosome state as a diagnostic tool for further refining the culture conditions of naive hPSCs.