Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis
Tissue mechanical properties are determined mainly by the extracellular matrix (ECM) and actively maintained by resident cells. Despite its broad importance to biology and medicine, tissue mechanical homeostasis remains poorly understood. To explore cell-mediated control of tissue stiffness, we developed mutations in the mechanosensitive protein talin 1 to alter cellular sensing of ECM. Mutation of a mechanosensitive site between talin 1 rod-domain helix bundles R1 and R2 increased cell spreading and tension exertion on compliant substrates. These mutations promote binding of the ARP2/3 complex subunit ARPC5L, which mediates the change in substrate stiffness sensing. Ascending aortas from mice bearing these mutations showed less fibrillar collagen, reduced axial stiffness, and lower rupture pressure. Together, these results demonstrate that cellular stiffness sensing contributes to ECM mechanics, directly supporting the mechanical homeostasis hypothesis and identifying a mechanosensitive interaction within talin that contributes to this mechanism.
Authors
- TuKiet T. Lam (ORCID: https://orcid.org/0000-0002-4850-3462)
- Dar Weiss (ORCID: https://orcid.org/0000-0001-6097-6038)
- Jay D. Humphrey (ORCID: https://orcid.org/0000-0003-1011-2025)
- Udo D. Schwarz (ORCID: https://orcid.org/0000-0002-5361-0342)
- X. F. Wang (ORCID: https://orcid.org/0000-0003-2846-9946)
- Manasa Chanduri (ORCID: https://orcid.org/0000-0002-9353-1438)
- Nir Emuna (ORCID: https://orcid.org/0000-0003-0695-8888)
- Abhishek Kumar (ORCID: https://orcid.org/0000-0003-3235-1916)
- Florine Collin (ORCID: https://orcid.org/0009-0007-7162-7360)
- Jean E. Kanyo (ORCID: https://orcid.org/0000-0003-4814-7573)
- Igor Barsukov (ORCID: https://orcid.org/0000-0003-4406-9803)
- Amit Datye (ORCID: https://orcid.org/0000-0002-1776-0642)
- Timothy Nottoli (ORCID: https://orcid.org/0000-0002-2218-5590)
- Benjamin T. Goult (ORCID: https://orcid.org/0000-0002-3438-2807)
- Suxia Bai
- Keiichiro Tanaka (ORCID: https://orcid.org/0000-0001-6328-1485)
- Martin Alexander Schwartz (ORCID: https://orcid.org/0000-0002-2071-1243)
- Miusi Shi (ORCID: https://orcid.org/0000-0001-8679-4013)
Institutions
- University of Liverpool (GB)
- University of Kent (GB)
- W. M. Keck Foundation (US)
- Yale University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1126/sciadv.adi6286
- Citations
- 15
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 4.89
Funders
- Yale University
- National Institutes of Health