1. Disrupting biological sensors of force promotes tissue regeneration in large organisms.
- Author
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Chen K, Kwon SH, Henn D, Kuehlmann BA, Tevlin R, Bonham CA, Griffin M, Trotsyuk AA, Borrelli MR, Noishiki C, Padmanabhan J, Barrera JA, Maan ZN, Dohi T, Mays CJ, Greco AH, Sivaraj D, Lin JQ, Fehlmann T, Mermin-Bunnell AM, Mittal S, Hu MS, Zamaleeva AI, Keller A, Rajadas J, Longaker MT, Januszyk M, and Gurtner GC
- Subjects
- Animals, Cell Differentiation, Cells, Cultured, Collagen metabolism, Female, Fibroblasts, Focal Adhesion Kinase 1 antagonists & inhibitors, Focal Adhesion Kinase 1 metabolism, Guided Tissue Regeneration, Humans, Indoles blood, Mechanotransduction, Cellular drug effects, Sequence Analysis, RNA, Single-Cell Analysis, Skin drug effects, Skin pathology, Skin Physiological Phenomena, Stress, Mechanical, Sulfonamides blood, Swine, Wound Healing drug effects, Indoles pharmacology, Mechanotransduction, Cellular physiology, Skin injuries, Sulfonamides pharmacology, Wound Healing physiology
- 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., (© 2021. The Author(s).)
- Published
- 2021
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