The YAP/TAZ–Tgfbr2–Stiffness Feedback Loop Governs Divergent Cell Fates of Muscle-Resident Mesenchymal Progenitors

Authors:
  • KIKanako Iwamori
    Kanako Iwamori
  • MHMomoka Horikiri
    Momoka Horikiri
  • AKAtsushi Kubo
    Atsushi Kubo
  • KTKosuke Tokiwa
    Kosuke Tokiwa
  • NSNanami Sakurai
    Nanami Sakurai
  • DMDaiki Mori
    Daiki Mori
  • ANAyasa Nakamura
    Ayasa Nakamura
  • MKMiyu Kimura
    Miyu Kimura
  • NTNana Taniguchi
    Nana Taniguchi
  • TKTamaki Kurosawa
    Tamaki Kurosawa
  • LZLidan Zhang
    Lidan Zhang
  • SWShunichi Watanabe
    Shunichi Watanabe
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Abstract
Mesenchymal progenitors are essential for muscle regeneration, but also contribute to fat accumulation and fibrosis. Several extrinsic and intrinsic factors regulating adipogenic or fibrogenic differentiation of mesenchymal progenitors have been identified, but it remains unclear how different cues are integrated to determine cell fate. Here, we demonstrate that interstitial stiffness and the mechanosensitive hippo pathway regulate mesenchymal progenitor cell fate. Fat accumulation model reduces interstitial stiffness and nuclear YAP/TAZ-positive mesenchymal progenitors compared to a regeneration model, whereas YAP/TAZ deficiency in mesenchymal progenitors enhances fat deposition. Mechanistically, YAP/TAZ directly induce expression of the anti-adipogenic genes Aldh1a2 and Wnt5a, and the pro-fibrogenic gene Tgfbr2, mediating TGF-β binding. Loss of Tgfbr2 in mesenchymal progenitors reduced transient collagen deposition, decreased stiffness, and increased fat accumulation during regeneration. We propose a stiffness–YAP/TAZ–Tgfbr2–collagen regulatory loop governing mesenchymal progenitor cell fate and highlight its importance for optimal muscle regeneration.