Releasing YAP dysfunction-caused replicative toxicity rejuvenates mesenchymal stem cells

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.

Automated summary

It has been found that YAP dysfunction, independent of Hippo signaling, can cause chronological aging of stromal cells by affecting the integrity of the nuclear envelope. Additionally, YAP activity also controls another type of cellular senescence, replicative senescence, in the in vitro expansion of mesenchymal stromal cells (MSCs), but this is dependent on Hippo phosphorylation and involves NE integrity-independent downstream mechanisms. The findings suggest that YAP plays a role in regulating replicative toxicity, genome stability, and DNA damage response/repair to maintain the regenerative capabilities of MSCs.