Cellular microenvironments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors
Cellular microenvironments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors
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DOI：
10.1242/jcs.144907
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发表时间：
2014-07-01
影响因子：
4
通讯作者：
Coirault, Catherine
中科院分区：
文献类型：
--
作者：
Bertrand, Anne T.;Ziaei, Simindokht;Coirault, Catherine
细胞对机械力的反应机制对肌肉发育和功能至关重要。我们的目的是确定是否突变的LMNA基因（编码核纤层蛋白A/C）导致先天性肌营养不良症损害肌肉前体的能力，感觉组织硬度和响应机械的挑战。我们发现LMNA突变的成肌细胞包埋在软基质中并不沿凝胶轴沿着，而对照组成肌细胞则如此。LMNA突变的成肌细胞无法调整其细胞骨架张力的组织硬度证明不适当的细胞基质粘附位点和细胞骨架张力在软与刚性基板或机械挑战后。重要的是，在软二维（2D）和/或静态三维（3D）条件下，LMNA突变的成肌细胞显示增强的yes相关蛋白（雅普）信号通路的激活，这是矛盾的循环拉伸后减少。siRNA介导的雅普下调减少了LMNA成肌细胞中的粘附和肌动蛋白应力纤维。这是第一次证明具有LMNA突变的人类成肌细胞通过YAP依赖性途径具有机械传感缺陷。此外，我们的数据强调了细胞微环境的生物物理属性对LMNA突变的成肌细胞中机械传感通路的响应的关键作用。
The mechanisms underlying the cell response to mechanical forces are crucial for muscle development and functionality. We aim to determine whether mutations of the LMNA gene (which encodes lamin A/C) causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts embedded in soft matrix did not align along the gel axis, whereas control myoblasts did. LMNA-mutated myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft two-dimensional (2D) and/or static three-dimensional (3D) conditions, LMNA-mutated myoblasts showed enhanced activation of the yes-associated protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. siRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in LMNA-mutated myoblasts.