Ma Nuoying, Chen Delia, Lee Ji-Hyung, Kuri Paola, Hernandez Edward Blake, Kocan Jacob, Mahmood Hamd, Tichy Elisia D, Rompolas Panteleimon, Mourkioti Foteini
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bioengineering Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Adv. 2022 Mar 18;8(11):eabn0485. doi: 10.1126/sciadv.abn0485.
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.
肌肉干细胞（MuSCs）对于组织稳态和再生至关重要，但MuSC形态对体内功能的潜在贡献仍不清楚。在这里，我们证明静止的MuSCs在形态上是异质的，并表现出不同的细胞突起模式。我们将静止的MuSCs分为三种功能不同的干细胞状态：反应性、中间性和感觉性。我们证明不同干细胞状态之间的转变促进再生，并受传感蛋白Piezo1的调节。Piezo1的药理学激活足以使MuSCs向更具反应性的细胞转变。MuSCs中Piezo1的缺失使分布向反应性较低的细胞转移，模拟了我们在营养不良肌肉中发现的疾病表型。我们进一步证明Piezo1的重新激活改善了营养不良肌肉的MuSC形态和再生缺陷。这些发现推进了我们对干细胞如何对损伤做出反应的基本理解，并确定Piezo1是调节再生所必需的干细胞状态的关键调节因子。
