Abstract
The skin expansion technique is widely used to induce skin growth for large‐scale skin deformity reconstruction. However, the capacity for skin expansion is limited and searching for ways to improve the expansion efficiency is a challenge. In this study, we aimed to explore the possible mechanism of skin expansion and to find a potential therapeutic target on promoting skin growth. We conducted weighted gene coexpression network analysis (WGCNA) of microarray data generated from rat skin expansion and found CCN1 (CYR61) to be the central hub gene related to epithelial‐mesenchymal transition (EMT). CCN1 up‐regulation was confirmed in human and rat expanded skin and also in mechanically stretched rat keratinocytes, together with acquired mesenchymal phenotype. After CCN1 stimulation on keratinocytes, cell proliferation was promoted and partial EMT was induced by activating β‐catenin pathway. Treatment of CCN1 protein could significantly increase the flap thickness, improve the blood supply and restore the structure in a rat model of skin expansion, whereas inhibition of CCN1 through shRNA interference could dramatically reduce the efficiency of skin expansion. Our findings demonstrate that CCN1 plays a crucial role in skin expansion and that CCN1 may serve as a potential therapeutic target to promote skin growth and improve the efficiency of skin expansion.
Highlights
Skin expansion is a surgical technique that is widely applied in clinical situation for critical-sized skin defect reconstruction of post-burn or post-trauma scars, congenital deformities and tumour resection.[1,2] This method utilizes a balloon-like silicone expander to load continuous mechanical stretch onto the local skin to promote skin growth.[1,3] The additional skin tissue obtained by skin expansion is an ideal match for the skin defect due to its similarity in colour, texture and structure.[4]
3.1 | CCN1 (CYR61) is a central ‘hub’ gene in the network of module genes related to Epithelial-mesenchymal transition (EMT) during rat skin expansion
EMT is characterized by loss of the epithelial phenotype, with reduced expression of the cell adhesion protein, and an acquired mesenchymal phenotype accompanied by increased expression of.[16]
Summary
Skin expansion is a surgical technique that is widely applied in clinical situation for critical-sized skin defect reconstruction of post-burn or post-trauma scars, congenital deformities and tumour resection.[1,2] This method utilizes a balloon-like silicone expander to load continuous mechanical stretch onto the local skin to promote skin growth.[1,3] The additional skin tissue obtained by skin expansion is an ideal match for the skin defect due to its similarity in colour, texture and structure.[4]. The growth capacity of skin in response to stretching is limited (usually less than 2-3 times the original area).[5,6] Over-expansion usually results in complications such as flap thinness, infection, ischaemia. The basic principle of skin expansion is that mechanical stretch initiates a cascade of events that results in skin growth. Cells undergo partial EMT are thought to acquire stemness traits and can differentiate into various cell types.[18] It is reported that EMT has been shown to be induced after the application of biomechanical force.[19,20] Our previous work first found the existence of EMT in mouse-expanded skin tissue[19] and indicated that EMT is a crucial process in skin growth under mechanical stretch. We performed multiple in vitro and in vivo experiments to demonstrate the effect of the central hub gene on skin expansion and its underlying mechanism
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