Identification of biomechanical force as a novel inducer of epithelial-mesenchymal transition features in mechanical stretched skin.

Biomechanical cues of the microenvironment are recognized as potent regulators of cell behaviors. Skin regeneration induced by tissue expansion has been confirmed by results of experimental and clinical studies. However, it is still unknown whether skin regeneration induced by mechanical factor is the same biological process as skin morphogenesis during embryonic development. In order to explore the potential role of biomechanical force (BioF) in skin regeneration and whether epithelial-mesenchymal transition (EMT) is induced by BioF, continuous mechanical tension (CMT) at 10% elongation was applied to human keratinocytes in vitro for 12, 24, 48 and 72 hours. Cell proliferation and differentiation were analyzed, including the expression of markers of EMT: vimentin, FSP1, E-cadherin and N-cadherin. Normal and mechanical stretched skin specimens collected from mice were examined by immunofluorescence analysis and RT-PCR. We found that BioF promoted the proliferation and inhibited differentiation of keratinocytes in vitro. The expression of markers of EMT vimentin, FSP1, E-cadherin and N-cadherin were transiently up-regulated by BioF. Keratinocytes activation, epidermal thickening and EMT features were also observed in the stretched epidermis of mice, compared to normal mice. Furthermore, the mechanism of BioF induced EMT was found to be the enhanced autocrine effect of TNF-α, in part, and direct activation of the NF-κB pathway. Collectively, BioF promoted the proliferation of keratinocytes by transiently inducing some EMT features. BioF, as a vital biomechanical cue of the microenvironment of skin, was identified to be a novel inducer of EMT, regulating keratinocytes' proliferation, differentiation and homeostasis of skin tissue.