The YAP/TAZ-Tgfbr2-stiffness feedback loop governs divergent cell fates of muscle-resident mesenchymal progenitors
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. However, 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 reduced interstitial stiffness and nuclear YAP/TAZ-positive mesenchymal progenitors compared with a regeneration model, whereas YAP/TAZ deficiency in mesenchymal progenitors enhanced fat deposition. Mechanistically, YAP/TAZ induced expression of the anti-adipogenic genes Aldh1a2 and Wnt5a , and the pro-fibrogenic gene Tgfbr2 , which mediates 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.
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BibTeX
@article{iwamori2026yaptaztgfbr2stiffness,
title = {{The YAP/TAZ-Tgfbr2-stiffness feedback loop governs divergent cell fates of muscle-resident mesenchymal progenitors}},
author = {Kanako Iwamori and Momoka Horikiri and Atsushi Kubo and Kosuke Tokiwa and Taku Fukushima and Nanami Sakurai and Daiki Mori and Ayasa Nakamura and Miyu Kimura and Nana Taniguchi and Tamaki Kurosawa and Madoka Ikemoto-Uezumi and Lidan Zhang and Shuichi Watanabe and Hiroshi Y. Yoshikawa and Thomas Braun and Akiyoshi Uezumi and Takahisa Matsuzaki and So-ichiro Fukada},
journal = {Cell Reports},
year = {2026},
month = nov,
doi = {10.1016/j.celrep.2026.118246},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726013252},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The YAP/TAZ-Tgfbr2-stiffness feedback loop governs divergent cell fates of muscle-resident mesenchymal progenitors
AU - Kanako Iwamori
AU - Momoka Horikiri
AU - Atsushi Kubo
AU - Kosuke Tokiwa
AU - Taku Fukushima
AU - Nanami Sakurai
AU - Daiki Mori
AU - Ayasa Nakamura
AU - Miyu Kimura
AU - Nana Taniguchi
AU - Tamaki Kurosawa
AU - Madoka Ikemoto-Uezumi
AU - Lidan Zhang
AU - Shuichi Watanabe
AU - Hiroshi Y. Yoshikawa
AU - Thomas Braun
AU - Akiyoshi Uezumi
AU - Takahisa Matsuzaki
AU - So-ichiro Fukada
PY - 2026
DA - 2026/11/01
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118246
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726013252
AB - 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. However, 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 reduced interstitial stiffness and nuclear YAP/TAZ-positive mesenchymal progenitors compared with a regeneration model, whereas YAP/TAZ deficiency in mesenchymal progenitors enhanced fat deposition. Mechanistically, YAP/TAZ induced expression of the anti-adipogenic genes Aldh1a2 and Wnt5a , and the pro-fibrogenic gene Tgfbr2 , which mediates 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.
SN - 2211-1247
ER -