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Mechanotransduction and extracellular matrix homeostasis

Nature Reviews Molecular Cell Biology volume 15, pages 802–812 (2014)Cite this article

Subjects

Key Points

  • Under steady state conditions, cells must actively maintain the mechanical properties of the extracellular matrix (ECM) to maintain the normal function of many, if not all, tissues.

  • Cells control ECM mechanics through degradation, synthesis, organization and pre-stress of its components.

  • Mechanical cues from the ECM trigger signalling cascades that alter gene expression and affect various processes, including cell motility and fate.

  • Elucidating the feedback mechanisms between cells and the ECM that maintain mechanical properties is a key question for future work.

Abstract

Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

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Figure 1: Key components in mechanical homeostasis of soft connective tissue.
Figure 2: Feedback control loops regulate extracellular matrix structure and function.
Figure 3: Cell–extracellular matrix interactions in health and disease.
Figure 4: Force-mediated regulation of integrin adhesions.

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Acknowledgements

Work in the authors' laboratories was supported, in part, by grants from the US National Institutes of Health (R01 HL105297 to J.D.H. and PO1 GM98412 to M.A.S.), US National Science Foundation (CMMI-116142 to J.D.H.), Sackler Program at Yale University (to E.R.D. and J.D.H.) and the Connecticut Stem Cell Fund grant 12SCA09 (to E.R.D.).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University,

    Jay D. Humphrey & Martin A. Schwartz

  2. Department of Mechanical Engineering, Yale University,

    Eric R. Dufresne

  3. Department of Cell Biology, Yale University,

    Eric R. Dufresne & Martin A. Schwartz

  4. Department of Medicine, Yale University, New Haven, 06520, Connecticut, USA

    Martin A. Schwartz

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  1. Jay D. Humphrey
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Correspondence to Martin A. Schwartz.

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Glossary

Homeostasis

An active promotion of equilibrium by biological systems. Homeostasis is a process, not a state. It requires both a sensor and an effector mechanism.

Integrins

Heterodimeric transmembrane protein complexes that are fundamental to mechanically linking the extracellular matrix to the cytoskeleton, and particularly to actin filaments.

Integrin linker proteins

Intracellular proteins, such as talin, filamin, α-actinin, PINCH, parvin, vinculin and paxillin, that provide vital links between the cytosolic domain of integrins and the cytoskeleton.

Williams syndrome

A genetic disorder resulting from the deletion of multiple genes on chromosome 7, including the gene encoding elastin, that results in cardiovascular disease and neurodevelopmental problems.

Marfan syndrome

A genetic disorder that affects connective tissues throughout the body, particularly in the heart, blood vessels, bones, joints and eyes. The affected extracellular matrix glycoprotein is fibrillin 1.

Osteogenesis imperfecta

A genetic disorder that presents as eight types, having mild to lethal consequences. It results primarily from mutations that affect collagen type I and leads to brittle bones, among other effects.

Ehlers–Danlos syndrome

A group of six heritable disorders caused by different defects in the synthesis of collagen, all of which exhibit joint laxity, fragile skin and easy bruising.

Mechanotransduction

Conversion of mechanical stimuli into biochemical information by cells.

Actomyosin

Combination of thin (actin) and thick (myosin) cytoskeletal filaments that enable forceful contractions powered by ATP. Inclusion of smooth muscle β-actin into actomyosin structures based on non-muscle myosin results in stress fibres that contract more forcefully.

Fibropositors

Membrane-associated structures in embryonic cells that aid in the organized deposition of collagen within the extracellular space. They depend on actomyosin activity.

Catch bond

A small fraction of molecular bonds that strengthen under force. Most molecular bonds, covalent or non-covalent, increase their off rates under tension, exhibiting so-called 'slip bond' behaviour, with the bond weakening under force. In the case of catch bonds, off rates decrease under tension (within a certain range), thus strengthening under force.

Quasi-static

A dynamic process that nevertheless occurs slowly enough that it can be considered as a series of equilibria.

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Humphrey, J., Dufresne, E. & Schwartz, M. Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15, 802–812 (2014). https://doi.org/10.1038/nrm3896

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