Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states

Muscle stem cells (MuSCs) are essential for tissue homeostasis and regeneration, but the potential contribution of MuSC morphology to in vivo function remains unknown. Here, we demonstrate that quiescent MuSCs are morphologically heterogeneous and exhibit different patterns of cellular protrusions. We classified quiescent MuSCs into three functionally distinct stem cell states: responsive, intermediate, and sensory. We demonstrate that the shift between different stem cell states promotes regeneration and is regulated by the sensing protein Piezo1. Pharmacological activation of Piezo1 is sufficient to prime MuSCs toward more responsive cells. Piezo1 deletion in MuSCs shifts the distribution toward less responsive cells, mimicking the disease phenotype we find in dystrophic muscles. We further demonstrate that Piezo1 reactivation ameliorates the MuSC morphological and regenerative defects of dystrophic muscles. These findings advance our fundamental understanding of how stem cells respond to injury and identify Piezo1 as a key regulator for adjusting stem cell states essential for regeneration.

Automated summary

This study reveals the morphological heterogeneity of muscle stem cells (MuSCs) and their different functional states. The shift between these states, regulated by the sensing protein Piezo1, promotes tissue regeneration. Activation of Piezo1 increases the responsiveness of MuSCs, while deletion of Piezo1 decreases their responsiveness. These findings enhance our understanding of how stem cells respond to injury and identify Piezo1 as a key regulator of the essential stem cell states for regeneration.