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Energy Expenditure during Cell Spreading Regulates the Stem Cells Responses to Matrix Stiffness
bioRxiv - Cell Biology Pub Date : 2021-01-11 , DOI: 10.1101/852400
Jing Xie , Min Bao , Xinyu Hu , Werner J. H. Koopman , Wilhelm T. S. Huck

Cells respond to the mechanical properties of the extracellular matrix (ECM) through the formation of focal adhesions (FAs), re-organization of the actin cytoskeleton, and adjustment of cell contractility. These are energy-demanding processes, but a potential causality between mechanical cues (matrix stiffness) and cellular (energy) metabolism remains largely unexplored. Here, we culture human mesenchymal stem cells (hMSCs) on stiff (20 kPa) or soft (1 kPa) substrate and demonstrate that cytoskeletal reorganization and FA formation spreading on stiff substrates lead to a drop in intracellular ATP levels, correlates with the activation of AMP-activated protein kinase (AMPK). The resulting increase in ATP levels further facilitates cell spreading and reinforces cell tension of the steady state, and coincides with nuclear localization of YAP/TAZ and Runx2. While on soft substrates (1 kPa), lowered ATP levels limit these cellular mechanoresponses. Furthermore, genetic ablation of AMPK lowered cellular ATP levels on the stiff substrate and strongly reduced responses to substrate stiffness. Together, these findings reveal a hitherto unidentified relationship between energy expenditure and the cellular mechanoresponse, and point to AMPK as a key mediator of stem cell fate in response to ECM mechanics.

中文翻译:

细胞扩散过程中的能量消耗调节干细胞对基质刚度的响应

细胞通过形成粘着斑(FAs),重组肌动蛋白细胞骨架和调节细胞收缩力来响应细胞外基质(ECM)的机械特性。这些都是耗能的过程,但是机械线索(矩阵刚度)与细胞(能量)代谢之间的潜在因果关系仍未得到充分探究。在这里,我们在硬质(20 kPa)或软质(1 kPa)底物上培养人间充质干细胞(hMSCs),并证明细胞骨架重组和FA形成在硬底物上扩散会导致细胞内ATP水平下降,并与活化AMP激活的蛋白激酶(AMPK)。ATP含量的增加进一步促进了细胞扩散并增强了稳态细胞的张力,并与YAP / TAZ和Runx2的核定位相吻合。在柔软的底物(1 kPa)上,较低的ATP含量限制了这些细胞的机械反应。此外,AMPK的遗传消融降低了刚性基质上的细胞ATP水平,并大大降低了对基质刚性的反应。总之,这些发现揭示了能量消耗与细胞机械反应之间迄今尚未确定的关系,并指出AMPK是响应ECM机制的干细胞命运的关键介质。
更新日期:2021-01-12
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