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Review
. 2018 Jan 2;128(1):74-84.
doi: 10.1172/JCI93561. Epub 2018 Jan 2.

Mechanosensing and fibrosis

Daniel J Tschumperlin  1 , Giovanni Ligresti  1 , Moira B Hilscher  2 , Vijay H Shah  2
Affiliations
Review

Mechanosensing and fibrosis

Daniel J Tschumperlin et al. J Clin Invest. .

Abstract

Tissue injury disrupts the mechanical homeostasis that underlies normal tissue architecture and function. The failure to resolve injury and restore homeostasis gives rise to progressive fibrosis that is accompanied by persistent alterations in the mechanical environment as a consequence of pathological matrix deposition and stiffening. This Review focuses on our rapidly growing understanding of the molecular mechanisms linking the altered mechanical environment in injury, repair, and fibrosis to cellular activation. In particular, our focus is on the mechanisms by which cells transduce mechanical signals, leading to transcriptional and epigenetic responses that underlie both transient and persistent alterations in cell state that contribute to fibrosis. Translation of these mechanobiological insights may enable new approaches to promote tissue repair and arrest or reverse fibrotic tissue remodeling.

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Conflict of interest statement

Conflict of interest: V.H. Shah is a consultant for Novartis. D.J. Tschumperlin reports research funding from MedImmune.

Figures

Figure 1
Figure 1. Physical and matrix changes in injury and fibrosis.
This schematic shows a prototypical interstitial ECM compartment bounded by endothelial and epithelial barriers. At homeostasis, reciprocal interactions between these compartments maintain tissue integrity and function. Injury alters mechanical homeostasis via barrier compromise (endothelial and epithelial disintegrity), cell invasion, cell-generated forces, elevated externally applied stretch, shear, and pressure, as well as ECM deposition, compositional changes, and interstitial pressure changes. While transient perturbations of mechanical homeostasis promote fibroblast functions essential to normal wound healing, impaired healing or failure to resolve injury can lead to a persistently altered mechanical environment. In the absence of restoration of normal homeostatic mechanical and intercellular interactions, matrix stiffening promotes persistent cellular dysfunction and activation, leading to ongoing cycles of matrix deposition and stiffening.
Figure 2
Figure 2. Mechanosensing mechanisms in injury, repair, and fibrosis.
Cells receive mechanical cues via mechanosensitive proteins at the cell membrane–cytoskeletal cortex interface (e.g., PIEZO1/2), as well as cell-cell and cell-matrix adhesions, with cadherins and integrins being the most common mechanical signaling interfaces. Mechanical signal processing occurs through adhesion protein clustering, stabilization of protein-protein interactions (e.g., integrin-talin), and activation of biochemical and transcriptional signaling pathways. These signals may initiate at cell-cell or cell-matrix adhesion sites, or as a consequence of cytoskeletal remodeling (actin, myosin, Rho/ROCK) within the cytoplasm. Cytoskeletal remodeling can also transmit forces across the nuclear envelope (nesprins, lamins), potentially directly altering the environment for transcription. The combination of forces directly transmitted to the nucleus and the nuclear localization of mechanoactivated transcriptional regulators combine with a variety of epigenetic mechanisms to transiently or persistently alter cellular programs that drive injury, repair, and fibrosis responses.
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