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Mechanosensing and fibrosis
Daniel J. Tschumperlin, … , Moira B. Hilscher, Vijay H. Shah
Daniel J. Tschumperlin, … , Moira B. Hilscher, Vijay H. Shah
Published January 2, 2018
Citation Information: J Clin Invest. 2018;128(1):74-84. https://doi.org/10.1172/JCI93561.
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Review Series

Mechanosensing and fibrosis

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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.

Authors

Daniel J. Tschumperlin, Giovanni Ligresti, Moira B. Hilscher, Vijay H. Shah

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Figure 2

Mechanosensing mechanisms in injury, repair, and fibrosis.

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Mechanosensing mechanisms in injury, repair, and fibrosis.
Cells receive...
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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ISSN: 0021-9738 (print), 1558-8238 (online)

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