Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states.
Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states.
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Piezo1通过协调干细胞形态状态调节骨骼肌的再生能力。
DOI：
10.1126/sciadv.abn0485
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发表时间：
2022-03-18
期刊：
影响因子：
13.6
通讯作者：
Mourkioti F
中科院分区：
文献类型：
--
作者：
Ma N;Chen D;Lee JH;Kuri P;Hernandez EB;Kocan J;Mahmood H;Tichy ED;Rompolas P;Mourkioti F
肌肉干细胞（Muscle Stem Cells，MuSC）是维持组织稳态和再生的关键细胞，但MuSC形态对体内功能的潜在作用尚不清楚。在这里，我们证明了静止的MuSCs是形态异质性的，并表现出不同的细胞突起模式。我们将静止的MuSC分为三种功能不同的干细胞状态：反应性、中间和感觉性。我们证明，不同的干细胞状态之间的转变促进再生，并通过传感蛋白Piezo1调节。Piezo1的药理学激活足以使MuSC向更具响应性的细胞转化。MuSC中的Piezo1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，并将Piezo1确定为调节再生所必需的干细胞状态的关键调节因子。Piezo1调节肌肉干细胞再生过程中的功能力学特性。
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. Piezo1 regulates functional mechanoproperties of muscle stem cells during regeneration.