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Releasing YAP dysfunction-caused replicative toxicity rejuvenates mesenchymal stem cells

Fanyuan Yu1,2, Lin Yao1,2, Feifei Li1

  • 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Aging Cell
|June 21, 2023
PubMed

Insights

YAP dysfunction causes cell aging. Hippo-dependent YAP activity controls replicative senescence in mesenchymal stromal cells (MSCs) by regulating cell cycle and DNA repair, with mutations rejuvenating MSCs.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Aging Research

Background:

  • Hippo-independent YAP dysfunction impairs nuclear envelope integrity, leading to chronological aging in stromal cells.
  • Cellular senescence, particularly replicative senescence in mesenchymal stromal cells (MSCs), is a critical factor in aging.

Purpose of the Study:

  • To investigate the Hippo phosphorylation-dependent role of YAP in replicative senescence of MSCs.
  • To elucidate the downstream mechanisms of YAP in controlling cellular senescence and genome stability.

Main Methods:

  • Utilized in vitro expansion of MSCs to study replicative senescence.
  • Employed Hippo-off YAP mutations (YAPS127A/S381A) to assess YAP's function.
  • Analyzed YAP/TEAD's regulation of RRM2 expression and its impact on cell cycle progression.
  • Investigated YAP's control over replicative toxicity (RT) transcriptomics and DNA damage response/repair pathways.

Main Results:

  • Hippo phosphorylation reduces nuclear YAP, decreasing YAP protein levels and initiating replicative senescence.
  • YAP/TEAD governs RRM2 expression, facilitating G1/S transition and releasing replicative toxicity.
  • YAP modulates RT transcriptomics, delaying genome instability and enhancing DNA repair.
  • Hippo-off YAP mutations rejuvenated MSCs by maintaining cell cycle, reducing genome instability, and restoring regenerative capacity without tumorigenesis risks.

Conclusions:

  • YAP activity, modulated by Hippo phosphorylation, plays a crucial role in replicative senescence of MSCs through NE integrity-independent pathways.
  • Targeting YAP signaling offers a potential strategy for rejuvenating aged cells and restoring tissue function.
Keywords:
DNA damageagingmesenchymal stromal cellrejuvenationreplicative stress

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