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

Xie, Jing and Bao, Min and Hu, Xinyu and Koopman, Werner J. H. and Huck, Wilhelm T. S. (2021) Energy expenditure during cell spreading influences the cellular response to matrix stiffness. Biomaterials, 267 . Art. No. 120494. ISSN 0142-9612.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription Paper
Bao, Min0000-0003-0992-9388
Huck, Wilhelm T. S.0000-0003-4222-5411
Alternate Title:Energy Expenditure during Cell Spreading Regulates the Stem Cells Responses to Matrix Stiffness
Additional Information:© 2020 Published by Elsevier Ltd. Received 6 July 2020, Revised 20 October 2020, Accepted 23 October 2020, Available online 24 October 2020. We thank José M. A. Hendriks for assistance with cell cultures, and Dr. Liesbeth Pierson for assistance with confocal microscopy. We thank Dr. Benoit Viollet (Paris Descartes University) for providing WT-MEF and AMPKα-null MEF cell lines. J.X., M.B. and X.H. would like acknowledge the department of General Instruments of the Radboud University for providing confocal and light microscopy services. We acknowledge financial support from the China Scholarship Council (J.X. and X.H.) and the Radboud Nanomedicine Alliance (M.B.). Credit author statement: Jing Xie, Conceptualization, Methodology, Investigation, Writing - original draft, Min Bao, Methodology, Investigation, Writing - original draft. Xinyu Hu, Investigation, Writing - review & editing. Werner J. H. Koopman, Methodology, Writing - review & editing. Wilhelm T. S. Huck, Supervision, Writing - original draft, Writing - review & editing Declaration of competing interest: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: W.J.H.K. is a scientific advisor of Khondrion B.V. (Nijmegen, The Netherlands) . This SME\ SME had no involvement in the data collection, analysis and interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication.
Funding AgencyGrant Number
China Scholarship CouncilUNSPECIFIED
Radboud Nanomedicine AllianceUNSPECIFIED
Subject Keywords:Energy expenditure; Cellular mechanoresponse; Substrate stiffness; AMPK activation
Record Number:CaltechAUTHORS:20201027-135828428
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Official Citation:Jing Xie, Min Bao, Xinyu Hu, Werner J.H. Koopman, Wilhelm T.S. Huck, Energy expenditure during cell spreading influences the cellular response to matrix stiffness, Biomaterials, Volume 267, 2021, 120494, ISSN 0142-9612, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106305
Deposited By: Tony Diaz
Deposited On:27 Oct 2020 21:21
Last Modified:20 Jan 2021 23:11

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