Disrupting biological sensors of force promotes tissue regeneration in large organisms

Kellen Chen, Sun Hyung Kwon, Dominic Henn, Britta A. Kuehlmann, Ruth Tevlin, Clark A. Bonham, Michelle Griffin, Artem A. Trotsyuk, Mimi R. Borrelli, Chikage Noishiki, Jagannath Padmanabhan, Janos A. Barrera, Zeshaan N. Maan, Teruyuki Dohi, Chyna J. Mays, Autumn H. Greco, Dharshan Sivaraj, John Q. Lin, Tobias Fehlmann, Alana M. Mermin-Bunnell, Smiti Mittal, Michael S. Hu, Alsu I. Zamaleeva, Andreas Keller, Jayakumar Rajadas, Michael T. Longaker, Michael Januszyk and Geoffrey C. Gurtner ()
Additional contact information
Kellen Chen: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Sun Hyung Kwon: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Dominic Henn: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Britta A. Kuehlmann: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Ruth Tevlin: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Clark A. Bonham: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Michelle Griffin: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Artem A. Trotsyuk: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Mimi R. Borrelli: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Chikage Noishiki: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Jagannath Padmanabhan: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Janos A. Barrera: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Zeshaan N. Maan: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Teruyuki Dohi: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Chyna J. Mays: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Autumn H. Greco: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Dharshan Sivaraj: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
John Q. Lin: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Tobias Fehlmann: Clinical Bioinformatics, Saarland University
Alana M. Mermin-Bunnell: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Smiti Mittal: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Michael S. Hu: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Alsu I. Zamaleeva: Biomaterials and Advanced Drug Delivery Laboratory, Stanford University
Andreas Keller: Clinical Bioinformatics, Saarland University
Jayakumar Rajadas: Biomaterials and Advanced Drug Delivery Laboratory, Stanford University
Michael T. Longaker: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Michael Januszyk: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
Geoffrey C. Gurtner: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25410-z

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