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

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

doi:10.1038/s41467-021-24383-3

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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.

Original language	English
Article number	4229
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24383-3
Publication status	Published - Dec 2021

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Andreu, I., Falcones, B., Hurst, S., Chahare, N., Quiroga, X., Le Roux, A. L., Kechagia, Z., Beedle, A. E. M., Elosegui-Artola, A., Trepat, X., Farré, R., Betz, T., Almendros, I., & Roca-Cusachs, P. (2021). The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening. Nature Communications, 12(1), [4229]. https://doi.org/10.1038/s41467-021-24383-3

@article{50efa56d7c474649acb21f832e9a6fb8,

title = "The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening",

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.",

author = "Ion Andreu and Bryan Falcones and Sebastian Hurst and Nimesh Chahare and Xarxa Quiroga and {Le Roux}, {Anabel Lise} and Zanetta Kechagia and Beedle, {Amy E.M.} and Alberto Elosegui-Artola and Xavier Trepat and Ramon Farr{\'e} and Timo Betz and Isaac Almendros and Pere Roca-Cusachs",

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), Fundaci{\'o} la Marat{\'o} 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. Gonz{\`a}lez-Tarrag{\'o} 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. Farr{\'e} 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. Ure{\~n}a for discussions. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-24383-3",

language = "English",

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Andreu, I, Falcones, B, Hurst, S, Chahare, N, Quiroga, X, Le Roux, AL, Kechagia, Z, Beedle, AEM, Elosegui-Artola, A, Trepat, X, Farré, R, Betz, T, Almendros, I & Roca-Cusachs, P 2021, 'The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening', Nature Communications, vol. 12, no. 1, 4229. https://doi.org/10.1038/s41467-021-24383-3

TY - JOUR

T1 - The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening

AU - Andreu, Ion

AU - Falcones, Bryan

AU - Hurst, Sebastian

AU - Chahare, Nimesh

AU - Quiroga, Xarxa

AU - Le Roux, Anabel Lise

AU - Kechagia, Zanetta

AU - Beedle, Amy E.M.

AU - Elosegui-Artola, Alberto

AU - Trepat, Xavier

AU - Farré, Ramon

AU - Betz, Timo

AU - Almendros, Isaac

AU - Roca-Cusachs, Pere

N1 - 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.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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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U2 - 10.1038/s41467-021-24383-3

DO - 10.1038/s41467-021-24383-3

M3 - Article

AN - SCOPUS:85109710194

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4229

ER -

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

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