Hepatocyte growth factor in biosheets promotes autonomous regeneration of cutaneous tissue after transplantation onto a full-thickness skin defect

Biosheets and biotubes are collagenous connective tissue membranes that surround unabsorbable molds embedded in living tissues, and can regenerate damaged tissues in various organs following in-situ transplantation. However, the mechanisms underlying tissue regeneration are still unclear. In this study, we analyzed the histological features and cellular composition in the biosheets, and observed dramatic time-dependent changes. We transplanted biosheets into full-thickness wounds in a mouse model, and evaluated skin regeneration through histological analysis in comparison with subcutaneous fascia transplantation. Our findings confirm that biosheets can accelerate epithelialization of skin wounds of mouse more effectively than fascia. To elucidate the mechanism underlying skin regeneration by biosheets, we compared the protein expression in the biosheets and subcutaneous fascia. Proteomics analysis revealed significant differences in the protein profiles of the biosheets and fascia, with marked elevation of hepatocyte growth factor (HGF) in the biosheets. Addition of HGF in situ accelerated angiogenesis and epithelial regeneration in the fascia-transplanted full-thickness wounds in mice. On the other hand, neutralization of HGF impaired the wound healing process following biosheet transplantation. In conclusion, our findings suggest that HGF mediates biosheet-mediated regeneration of cutaneous tissues by contributing to re-epithelialization and angiogenesis.