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The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening

Research output: Contribution to journalArticlepeer-review

Ion Andreu, Bryan Falcones, Sebastian Hurst, Nimesh Chahare, Xarxa Quiroga, Anabel Lise Le Roux, Zanetta Kechagia, Amy E.M. Beedle, Alberto Elosegui-Artola, Xavier Trepat, Ramon Farré, Timo Betz, Isaac Almendros, Pere Roca-Cusachs

Original languageEnglish
Article number4229
JournalNature Communications
Volume12
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: This work was supported by the Spanish Ministry of Science and Innovation (PID2019-110298GB-I00, PGC2018-099645-B-I00), the European Commission (H2020-FET-PROACT-01-2016-731957, and the Marie Sklodowska-Curie Grant Agreement No. 798504 to A.E.-A.), the Generalitat de Catalunya (2017-SGR-1602), Fundació la Marató de TV3 (201936-30-31 and 201903-30-31-32), the European Research Council (ERC-Adv 883739 to X.T.), the prize “ICREA Academia” for excellence in research to P.R.-C., and “la Caixa” Foundation (Agreement LCF/PR/HR20/52400004). S.H and T.B. were supported by the German Science Foundation (EXC 1003 CiM, Cells in Motion), the European Research Council (Consolidator Grants 771201, PolarizeMe), and the Human Frontier Science Program (HFSP grant RGP0018/2017). A.E.M.B. was supported by a Sir Henry Wellcome Fellowship (210887/Z/18/Z). IBEC is the recipient of a Severo Ochoa Award of Excellence from the Spanish Ministry of Science and Innovation. We thank V. Gonzàlez-Tarragó for assistance in experiments, set-up implementation, and discussions. We thank the members of P. Roca-Cusachs., X. Trepat, T. Betz, I. Almendros, and R. Farré laboratories for technical assistance and discussions. We thank M. Brandt and D. Navajas for their technical assistance and discussions. We thank A. Lahiguera and C. Ureña for discussions. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Cell response to force regulates essential processes in health and disease. However, the fundamental mechanical variables that cells sense and respond to remain unclear. Here we show that the rate of force application (loading rate) drives mechanosensing, as predicted by a molecular clutch model. By applying dynamic force regimes to cells through substrate stretching, optical tweezers, and atomic force microscopy, we find that increasing loading rates trigger talin-dependent mechanosensing, leading to adhesion growth and reinforcement, and YAP nuclear localization. However, above a given threshold the actin cytoskeleton softens, decreasing loading rates and preventing reinforcement. By stretching rat lungs in vivo, we show that a similar phenomenon may occur. Our results show that cell sensing of external forces and of passive mechanical parameters (like tissue stiffness) can be understood through the same mechanisms, driven by the properties under force of the mechanosensing molecules involved.

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