The role of REX1 in the maintenance and reacquisition of stem cell pluripotency

Abstract

Part I. REX1 positively contributes to the maintenance of hPSC self-renewal and pluripotency

Transcription factor REX1 is widely used as a stem cell marker, but its functions remain poorly understood. Here, we show that REX1 is an essential factor for the maintenance and the full differentiation potential of human embryonic stem cells (hESCs). Depletion of REX1 in hESCs leads to differentiation, reduced potential for mesoderm fate in vivo, growth inhibition, apoptosis and G2 arrest. Cyclin B1/B2 expression was found to parallel that of REX1. REX1 binds to cyclin B1/B2 promoters and regulates their transcriptional activity. REX1 induces the phosphorylation of Drp1 at Ser616 by cyclin B/CDK1, which leads to mitochondrial fission. REX1 contributes to a distinctive metabolic feature of highly glycolytic hESCs through promoting Drp1 fission activity; whereas upon REX1 depletion, there are changes into an elongated mitochondrial network within hESCs. These findings reveal a functional role for REX1 in the maintenance of stem cell pluripotency.

Part II. REX1 is an essential factor for the rapid and efficient reprogramming of human somatic cells into a pluripotent state

Human induced pluripotent stem cells (hiPSCs) can be reprogrammed from a variety of somatic cells using different combinations of defined factors. To date, however, there are several hurdles in this process, such as safety issues and low efficiency. Intrinsic REX1 is indispensable for reprogramming human somatic cells to pluripotency, and ectopic REX1 is beneficial for enhancing reprogramming efficiency and kinetics. REX1 facilitates the reprogramming process by enhancing cyclin B expression and Drp1 fission activity, affecting pluripotency. We also report that the REX1 can be employed to produce hiPSCs from various cell types without cell type-specific restrictions and can reduce the number of required reprogramming factors. Human neural progenitors and mesenchymal stem cells were efficiently and r...