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  • Review Article
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Modelling and targeting mechanical forces in organ fibrosis

Nature Reviews Bioengineering volume 2, pages 305–323 (2024)Cite this article

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Abstract

Few efficacious therapies exist for the treatment of fibrotic diseases, such as skin scarring, liver cirrhosis and pulmonary fibrosis, which is related to our limited understanding of the fundamental causes and mechanisms of fibrosis. Mechanical forces from cell–matrix interactions, cell–cell contact, fluid flow and other physical stimuli may play a central role in the initiation and propagation of fibrosis. In this Review, we highlight the mechanotransduction mechanisms by which various sources of physical force drive fibrotic disease processes, with an emphasis on central pathways that may be therapeutically targeted to prevent and reverse fibrosis. We then discuss engineered models of mechanotransduction in fibrosis, as well as molecular and biomaterials-based therapeutic approaches for limiting fibrosis and promoting regenerative healing phenotypes in various organs. Finally, we discuss challenges within fibrosis research that remain to be addressed and that may greatly benefit from next-generation bioengineered model systems.

Key points

  • Fibrosis — the replacement of normal tissues with matrix-rich connective tissue — is a common response to trauma, autoimmune reactions, radiation and other insults, and can occur in almost every organ.

  • Fibrotic disease is initiated and propagated by a variety of physical forces, including cell–matrix, cell–cell, osmotic and viscous, as well as physical confinement and nuclear forces.

  • Fibrosis models can be engineered to study mechanotransduction pathways specific to each type of physical force.

  • Molecular and biomaterials-based therapies have been developed to treat fibrosis by modulating mechanotransduction.

  • Multiomics analysis, next-generation models and biomaterials as well as advanced tools for the quantification of fibrosis will further advance fibrosis research.

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Fig. 1: Physical stimuli and associated downstream mechanotransduction signalling pathways.
Fig. 2: Biomaterials for the treatment and modelling of fibrosis.
Fig. 3: Mechanotransduction signalling targets in fibrosis.
Fig. 4: Platforms and molecular tools to study fibrosis.

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Acknowledgements

This work was supported by NIH R01-DE032677, NIH R01-AR081343, NIH F32-HL167318, NIH R01-GM136659, NIH U24-DE029463, NIH R01-DE027346, the Wu Tsai Human Performance Alliance, the Hagey Laboratory for Pediatric Regenerative Medicine, the Gunn Olivier Fund, the Scleroderma Research Foundation, and the Pitch and Catherine Johnson Fund.

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  1. These authors contributed equally: Shamik Mascharak, Jason L. Guo, Michelle Griffin.

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  1. Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA

    Shamik Mascharak, Jason L. Guo, Michelle Griffin, Charlotte E. Berry, Derrick C. Wan & Michael T. Longaker

  2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Shamik Mascharak, Jason L. Guo, Michelle Griffin & Michael T. Longaker

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Mascharak, S., L. Guo, J., Griffin, M. et al. Modelling and targeting mechanical forces in organ fibrosis. Nat Rev Bioeng 2, 305–323 (2024). https://doi.org/10.1038/s44222-023-00144-3

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