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.
Highlights
Tissue repair and healing remain among the most complicated processes that occur during postnatal life
We found that wounds treated with FAKI hydrogels (W_HF) had fully healed at postoperative day (POD) 14 ± 2.3, more than 10 days earlier than wounds treated with standard dressings (W) or empty hydrogels (W_H) (****p < 0.0001) (Fig. 1d, e)
Our study indicates that modulation of mechanotransduction can push and pull fibroblast programming either toward or away from fibrotic transcriptional states, highlighting the critical importance of mechanical forces in tissue regeneration
Summary
Tissue repair and healing remain among the most complicated processes that occur during postnatal life. 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. Rodents are several magnitudes smaller in mass than humans and experience lower tissue forces[7], and even though current wound models try to mimic human-like wound biology, these models still do not fully replicate human scar formation and fibrosis[12,14]. These fundamental differences have significantly limited the translational relevance of fibrosis studies performed in rodent models. To effectively translate therapies for human clinical use, we must thoroughly investigate potential therapies in both clinically relevant, large animal models as well as in human cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
