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

Abstract

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.

Membrane curvature governs the distribution of Piezo1 in live cells

“…Secondly, knocking out Piezo in Drosophila promotes axon regeneration 58 . Furthermore, Piezo1 negatively regulates the morphological activity (i.e., number of protrusions) of muscle stem cells 59 . Lastly, Piezo2 inhibits neurite outgrowth in N2A cells 17 .…”

“…Lastly, Piezo2 inhibits neurite outgrowth in N2A cells 17 . In addition to membrane curvature, several parallel Piezo-related mechanisms can regulate the formation and growth of filopodia, including Ca 2+ signaling induced by the activation of Piezo and potential interactions between specific Piezo domains with cytoskeletal components 17 , 58 , 59 . Our data do not exclude these parallel mechanisms, rather, we suggest that the curvature preference of Piezo1 provides an additional route to control filopodia dynamics.…”

The mechanosensitive ion channel PIEZO1 promotes satellite cell function in muscle regeneration

“…Recent studies have shown that PIEZO1 plays a role in MuSC function. Ma et al (2022) demonstrated that MuSCs are morphologically heterogeneous with axon-like protrusions and that PIEZO1 is essential for preserving this feature, thereby priming MuSCs to be more responsive. In this study, we have revealed that Piezo1 deficiency affects the Rho activation ( Fig 7A–C ).…”

The emergence of the stem cell niche

“…Interestingly, fetal acetylcholine receptors are re-expressed during regeneration throughout adult muscle [ 32 ], similar to what is seen in other niche systems. Structural maturation of fetal myofibers corresponds with changes to their plasma membrane, including expression of potassium-gated ion channels and calcium channels such as Piezo1 that regulate sarcolemma phospholipids and begin to assemble the components needed to build the SC niche [ 33 , 34 ]. Adult myofibers of the limb are made up of multiple myosins, which include MYH1 and MYH2 , unless they are undergoing regeneration, in which case they re-express embryonic and fetal myosin isoforms, such as what is seen in emerging niches in development.…”

“…In one of the most devastating muscle-wasting diseases, Duchenne muscular dystrophy (DMD), SCs deficient in dystrophin lose polarity and are unable to appropriately form a niche, leading to a dysfunctional progenitor state, failed regeneration, and/or disease exacerbation [ 108 ]. Recent work has shown that SCs survey their niche via cell protrusions [ 109 ], which, when impaired, such as in Piezo1 knockout or DMD, primes SCs to activate from quiescence [ 33 ].…”