Energy expenditure during cell spreading influences the cellular response to matrix stiffness

Jing Xie, Min Bao, Xinyu Hu, Werner J.H. Koopman, Wilhelm T.S. Huck*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

46 Citations (Scopus)

Abstract

Cells respond to the mechanical properties of the extracellular matrix (ECM) through 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 cultured 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, correlating with 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 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.

Original languageEnglish
Article number120494
JournalBiomaterials
Volume267
DOIs
Publication statusPublished - Jan 2021
Externally publishedYes

Keywords

  • AMPK activation
  • Cellular mechanoresponse
  • Energy expenditure
  • Substrate stiffness

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