Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load

• Published in: Cell stem cell Vol. 29; no. 2; pp. 265 - 280.e6
• Main Authors: Kaneshige, Akihiro, Kaji, Takayuki, Zhang, Lidan, Saito, Hayato, Nakamura, Ayasa, Kurosawa, Tamaki, Ikemoto-Uezumi, Madoka, Tsujikawa, Kazutake, Seno, Shigeto, Hori, Masatoshi, Saito, Yasuyuki, Matozaki, Takashi, Maehara, Kazumitsu, Ohkawa, Yasuyuki, Potente, Michael, Watanabe, Shuichi, Braun, Thomas, Uezumi, Akiyoshi, Fukada, So-ichiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2022
• Subjects: Animals; CalcR; CD47; CD47 Antigen - metabolism; Hypertrophy - metabolism; mechanical load; mesenchymal progenitors; Mice; muscle satellite cells; Muscle, Skeletal - metabolism; Myoblasts - metabolism; Stem Cells - metabolism; Taz; Thbs1; Yap; CalcR; muscle satellite cells; Yap; mechanical load; CD47; mesenchymal progenitors; Taz; Thbs1
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2021.11.003

Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for efficient muscle hypertrophy relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion under conditions of increased load are not fully understood. Here we demonstrate that interstitial mesenchymal progenitors respond to mechanical load and stimulate MuSC proliferation in a surgical mouse model of increased muscle load. Mechanistically, transcriptional activation of Yes-associated protein 1 (Yap1)/transcriptional coactivator with PDZ-binding motif (Taz) in mesenchymal progenitors results in local production of thrombospondin-1 (Thbs1), which, in turn, drives MuSC proliferation through CD47 signaling. Under homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Our results suggest that relayed signaling between mesenchymal progenitors and MuSCs through a Yap1/Taz-Thbs1-CD47 pathway is critical to establish the supply of MuSCs during muscle hypertrophy. [Display omitted] •Yap/Taz in mesenchymal progenitor cells of loaded muscles induce MuSC proliferation•Expression of Thbs1 in mesenchymal progenitors during overload depends on Yap/Taz•The Thbs1-CD47 axis regulates MuSC proliferation in overloaded muscles•CD47 activation induces MuSC proliferation in calcitonin receptor mutant muscles Kaneshige et al. revealed that initiation of muscle stem cell (MuSC) proliferation in overloaded muscles depends on YAP/TAZ activity in mesenchymal progenitors (MPs). Inactivation of YAP/TAZ in MPs or ablation of MPs blunts myonuclear accretion after mechanical loading. The crosstalk between MPs and MuSCs is mediated via the Thbs1-CD47 axis.