Releasing YAP dysfunction‐caused replicative toxicity rejuvenates mesenchymal stem cells

Abstract

Hippo‐independent YAP dysfunction has been demonstrated to cause chronological aging of stromal cells by impairing the integrity of nuclear envelope (NE). In parallel with this report, we uncover that YAP activity also controls another type of cellular senescence, the replicative senescence in in vitro expansion of mesenchymal stromal cells (MSCs), but this event is Hippo phosphorylation‐dependent, and there exist another NE integrity‐independent downstream mechanisms of YAP. Specifically, Hippo phosphorylation causes reduced nuclear/active YAP and then decreases the level of YAP protein in the proceeding of replicative senescence. YAP/TEAD governs RRM2 expression to release replicative toxicity (RT) via licensing G1/S transition. Besides, YAP controls the core transcriptomics of RT to delay the onset of genome instability and enhances DNA damage response/repair. Hippo‐off mutations of YAP (YAP ^S127A/S381A) satisfactorily release RT via maintaining cell cycle and reducing genome instability, finally rejuvenating MSCs and restoring their regenerative capabilities without risks of tumorigenesis.

Abstract

Fanyuan et al. revealed that YAP dysfunction occurred in the proceeding of MSCs expansion, which was the crucial driver of cellular senescence. YAP dysfunction reduced the regulatory transcriptome of cell cycle to arrest cells into G1 phase. This cycle arrest subsequently caused inevitable genome instability and impairment of DNA damage response, defined as replicative toxicity (RT). YAPS127A/S381A double‐mutation successfully prevented replicative senescence via releasing YAP dysfunction‐caused RT, and finally rejuvenated MSCs to sufficiently restore their regenerative capabilities.