Disrupting biological sensors of force promotes tissue regeneration in large organisms

Disrupting biological sensors of force promotes tissue regeneration in large organisms. Chen, K., Kwon, S., Henn, D., Kuehlmann, B., Tevlin, R., Bonham, C., Griffin, M., Trotsyuk, A., Borrelli, M., Noishiki, C., Padmanabhan, J., Barrera, J., Maan, Z., Dohi, T., Mays, C., Greco, A., Sivaraj, D., Lin, J., Fehlmann, T., Mermin-Bunnell, A. M., Mittal, S., Hu, M. S., Zamaleeva, A. I., Keller, A., Rajadas, J., Longaker, M. T., Januszyk, M., & Gurtner, G. Nature Communications, 12, 09, 2021.
doi abstract bibtex

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

@article{chens4146702125410z,
    author = {Chen, Kellen and Kwon, Sun and Henn, Dominic and Kuehlmann, Britta and Tevlin, Ruth and Bonham, Clark and Griffin, Michelle and Trotsyuk, Artem and Borrelli, Mimi and Noishiki, Chikage and Padmanabhan, Jagannath and Barrera, Janos and Maan, Zeshaan and Dohi, Teruyuki and Mays, Chyna and Greco, Autumn and Sivaraj, Dharshan and Lin, John and Fehlmann, Tobias and Mermin-Bunnell, Alana M. and Mittal, Smiti and Hu, Michael S. and Zamaleeva, Alsu I. and Keller, Andreas and Rajadas, Jayakumar and Longaker, Michael T. and Januszyk, Michael and Gurtner, Geoffrey},
    year = {2021},
    month = {09},
    pages = {},
    abstract = {Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.},
    title = {Disrupting biological sensors of force promotes tissue regeneration in large organisms},
    volume = {12},
    journal = {Nature Communications},
    doi = {10.1038/s41467-021-25410-z}
}

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