Mechanical Stretching Can Modify the Papillary Dermis Pattern and Papillary Fibroblast Characteristics during Skin Regeneration

Clinical application of mechanical stretching is a reconstructive method for skin repair. Although studies have reported dermal fibroblast heterogeneity, whether stretching affects individual fibroblast subpopulations equally remains unclear. In this study, we show the changes in dermal structure and papillary fibroblast (Fp) in regenerated human skin. Exhausted skin regeneration caused dermal‒epidermal junction flattening, papillary dermis thinning, and an increase in type III collagen-to-type I collagen ratio, with upregulated hallmarks of aging. Well-regenerated skin displayed a notable increase in the Fp population. Consistent changes were observed in the rat expansion model. Moreover, we found that TGFβ1 expression was especially increased in skin showing good regeneration. Activation of the TGFβ1/SMAD2/3 pathway improved exhausted skin regeneration and resulted in increased collagen content and Fp proliferation, whereas pharmacological inhibition of TGFβ1 action impacted well-regenerated skin. Short-term mechanical stretching that promoted skin regeneration enhanced Fp proliferation, extracellular matrix synthesis, and increased TGFβ1 expression, leading to good regeneration. Conversely, long-term stretching induced premature Fp senescence, leading to poor regeneration. This work shows the mechanism of mechanical stretching in well-skin regeneration that enhances Fp proliferation and extracellular matrix synthesis through the TGFβ1/SMAD2/3 pathway and highlights a crucial role of Fps in stretching-induced skin regeneration.