Cell response to extracellular matrix viscous energy dissipation outweighs high-rigidity sensing
The mechanics of the extracellular matrix (ECM) determine cell activity and fate through mechanoresponsive proteins including Yes-associated protein 1 (YAP). Rigidity and viscous relaxation have emerged as the main mechanical properties of the ECM steering cell behavior. However, how cells integrate coexisting ECM rigidity and viscosity cues remains poorly understood, particularly in the high-stiffness regime. Here, we have exploited engineered stiff viscoelastic protein hydrogels to show that, contrary to current models of cell-ECM interaction, substrate viscous energy dissipation attenuates mechanosensing even when cells are exposed to higher effective rigidity. This unexpected behavior is however readily captured by a pull-and-hold model of molecular clutch-based cell mechanosensing, which also recapitulates opposite cellular response at low rigidities. Consistent with predictions of the pull-and-hold model, we find that myosin inhibition can boost mechanosensing on cells cultured on dissipative matrices. Together, our work provides general mechanistic understanding on how cells respond to the viscoelastic properties of the ECM.
Authors
- Ricardo Esteban-González
- Diana Velázquez-Carreras (ORCID: https://orcid.org/0000-0002-0671-2549)
- Francisco M. Espinosa (ORCID: https://orcid.org/0000-0001-7716-0553)
- Carla Huerta-López (ORCID: https://orcid.org/0000-0002-6943-3475)
- Miguel Á. del Pozo (ORCID: https://orcid.org/0000-0001-9077-391X)
- Ricardo Garcı́a
- Pere Roca‐Cusachs (ORCID: https://orcid.org/0000-0001-6947-961X)
- Luis I. Gutierrez-Rus (ORCID: https://orcid.org/0000-0001-5521-1989)
- Gustavo R. Plaza (ORCID: https://orcid.org/0000-0002-5555-5498)
- María García-García (ORCID: https://orcid.org/0000-0002-1648-8659)
- Pablo Sáez (ORCID: https://orcid.org/0000-0002-9253-0417)
- Alberto Elósegui-Artola (ORCID: https://orcid.org/0000-0003-0644-3294)
- Álvaro Martínez‐del‐Pozo (ORCID: https://orcid.org/0000-0003-0043-5939)
- A. Blanco (ORCID: https://orcid.org/0000-0002-0034-8846)
- Francisco M. Martín-Zamora (ORCID: https://orcid.org/0000-0002-2558-3762)
- Elías Herrero‐Galán (ORCID: https://orcid.org/0000-0003-1916-6185)
- Alejandro Clemente-Manteca (ORCID: https://orcid.org/0000-0001-9385-4897)
- Sara Martín-Colomo (ORCID: https://orcid.org/0000-0002-6443-8226)
- J. García Sánchez (ORCID: https://orcid.org/0000-0003-1734-4531)
Institutions
- Universidad Complutense de Madrid (ES)
- King's College London (GB)
- The Francis Crick Institute (GB)
- Spanish National Centre for Cardiovascular Research (ES)
- Instituto de Ciencia de Materiales de Madrid (ES)
- Institute for Bioengineering of Catalonia (ES)
- Universitat de Barcelona (ES)
- Universidad Politécnica de Madrid (ES)
- Universitat Politècnica de Catalunya (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1126/sciadv.adf9758
- Citations
- 33
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 10.76