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Mechanotransduction inhibition prevents scarring and yields regeneration in a large animal model

ABSTRACT: Inhibiting mechanotransduction (via Yes-associated protein [YAP] inhibition) in mouse wounds yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We thus sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that a single treatment with the YAP inhibitor verteporfin, immediately following wounding, is sufficient to prevent scarring and drive wound regeneration in pigs. By performing scRNA-seq for the first time on porcine wounds in conjunction with spatial protein analysis, we reveal perturbations in fibroblast subpopulation profiles with verteporfin treatment and the presence of putative pro-regenerative and pro-fibrotic fibroblast subsets enriched in regenerating and scarring pig wounds, respectively. Finally, we validate our findings in a human foreskin xenograft wound model, including scRNA-seq of human wound cells. Collectively, our findings provide critical support for the future translation of local mechanotransduction inhibitors to prevent human skin scarring.

ORGANISM(S): Homo sapiens Sus scrofa

PROVIDER: GSE219158 | GEO | 2025/01/08

REPOSITORIES: GEO

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Project description:While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. We used microarray analysis to determine the gene expression changes that take place during scar free wound healing in aquatic and terrestrial axolotl salamanders. Epidermal tissue was harvested using a 4mm biopsy punch. Two wounds were made along the flank and posterior to the forelimbs. Harvested epidermis was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.

Project description:In adult mammals, skin wound healing has evolved to favor rapid repair through formation of fibrotic scar. Consequently, skin wounds are dysfunctional and lead to chronic disfigurement and disability, yet the biologic mechanisms that drive fibrosis and prevent tissue regeneration remain unknown. Here, we report that reindeer (Rangifer tarandus) antler velvet exhibits regenerative wound healing, whereas identical full-thickness injury in dorsal back skin forms fibrotic scar. This regenerative capacity is retained even following ectopic transplantation of velvet to a scar-forming site, demonstrating that this latent regenerative capacity is innate to velvet cells and independent of local factors derived from the growing antler. Single cell RNA-sequencing of uninjured skin revealed a marked divergence in resting fibroblast transcriptional states and immunomodulatory function. Uninjured velvet fibroblast shared a striking resemblance with human fetal fibroblasts whereas uninjured back skin fibroblasts exhibited an overrepresentation of pro-inflammatory genes resembling adult human fibroblasts. Identical skin injury resulted in site-specific fibroblast polarization; back fibroblasts exacerbated the inflammatory response, whereas velvet fibroblasts adopted an immunosuppressive state and reverted back to a regeneration-competent ground state. Consequently, velvet wounds exhibited reduced immune infiltrate, accelerated adoption of anti-inflammatory immune states and expedited resolution of immune response. This study demonstrates reindeer as a novel mammalian model to study adult skin regeneration (velvet) and scar formation (back skin) within the same animal. Our study underscores the importance of fibroblast heterogeneity in shaping local immune cell functions that ultimately polarize wound healing outcomes. Purposeful, acute modulation of fibroblast-mediated immune signaling represents an important therapeutic avenue to mitigate scar and improve wound healing.

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Mechanotransduction inhibition prevents scarring and yields regeneration in a large animal model

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