Disrupting biological sensors of force promotes tissue regeneration in large organisms
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 06, 2021
- Source ID
- 10.1038/s41467-021-25410-z
Entities
People
- Alana M. Mermin-Bunnell
- Alsu I. Zamaleeva
- Andreas Keller
- Artem A. Trotsyuk
- Autumn H. Greco
- Britta A. Kuehlmann
- Chikage Noishiki
- Chyna J. Mays
- Clark A. Bonham
- Dharshan Sivaraj
- Dominic Henn
- Geoffrey C. Gurtner
- Jagannath Padmanabhan
- Janos A. Barrera
- Jayakumar Rajadas
- John Q. Lin
- Kellen Chen
- Michael Januszyk
- Michael S. Hu
- Michael T Longaker
- Michelle Griffin
- Mimi R. Borrelli
- Ruth Tevlin
- Smiti Mittal
- Sun Hyung Kwon
- Teruyuki Dohi
- Tobias Fehlmann
- Zeshaan N. Maan
Organizations
- Armed Forces Institute of Regenerative Medicine
- National Institute of Dental and Craniofacial Research