CDH1 is Identified as A Therapeutic Target for Skin Regeneration after Mechanical Loading

Abstract

<b>Rationale:</b> Mechanical stimuli in the microenvironment are considered key regulators of cell function. Clinically, mechanical force (tissue expander) is widely used to regenerate skin for post-burn or trauma repair, implying that mechanical stretching can promote skin cell regeneration and proliferation. However, the underlying mechanism remains unknown. <b>Methods:</b> Microarray analysis was utilized to detect the hub gene. The expression of Cdh1 as examined in cells and tissues by western blot, q-PCR and immunohistochemistry staining respectively. Biological roles of Cdh1 was revealed by a series of functional in vitro and in vivo studies. <b>Results:</b> Microarray analysis identified <i>Cdh1</i> as a hub gene related to skin regeneration during rat cutaneous mechanical loading. In vitro studies suggested that both mechanical loading and <i>Cdh1</i> interference induced keratinocyte dedifferentiation and enhanced stemness, promoting cell proliferation and prevent apoptosis. Furthermore, the forkhead box O1/Krüppel-like factor 4 (FOXO1/KLF4) pathway was activated and contributed to the keratinocyte dedifferentiation. In vivo studies showed that mechanical loading and <i>Cdh1</i> interference facilitated epidermal dedifferentiation and promoted dermal collagen deposition, and that <i>Cdh1</i> overexpression could block such influence. <b>Conclusions:</b> In this study, we show that E-cadherin (CDH1), a well-known cell-cell adhesion molecule, plays a crucial role in mechanical stretch-induced skin cell regeneration and proliferation. We have shown for the first time the process by which mechanical stress is transmitted to the epidermis and induces a downstream signaling pathway to induce epidermal cells to differentiate. These findings demonstrate that <i>Cdh1</i>-induced keratinocyte dedifferentiation is a crucial event in mechanical stretch-mediated skin regeneration and that <i>Cdh1</i> may serve as a potential therapeutic target for promoting skin regeneration.