CCN1 Protein Promotes Mechanical-Stretch-Induced Skin Regeneration by Activating Epithelial-Mesenchymal Transition

Abstract

In clinical practice, mechanical stretch is widely used to regenerate skin for soft-tissue reconstruction, which is termed skin expansion. However, the ability of stretch-induced skin regeneration is limited and searching for ways to enhance the expansion efficacy is a major challenge. Here, we found that expression of the CCN family member 1 (CCN1) gene, also known as cysteine-rich angiogenic inducer 61 (CYR61), was elevated in expanded skin of both humans and rats, along with enhanced epithelial-mesenchymal transition (EMT). In vitro studies suggested that CCN1 could promote cell proliferation and prevent cell apoptosis, as well as inducing EMT directly in keratinocytes. In vivo studies elucidated that CCN1 protein could facilitate dedifferentiation of the epidermis and promote skin regeneration by activating EMT in rats. Furthermore, CCN1 protein was found to significantly increase the flap thickness, improve the blood supply and restore the structure in a rat model of skin expansion. In conclusion, our findings demonstrate that CCN1-induced EMT is a crucial event in mechanical-stretch-induced skin regeneration and that CCN1 may serve as a potential therapeutic target to promote skin regeneration and enhance the efficacy of skin expansion. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81501668, No. 81620108019 and No. 81230042). Declaration of Interests: The authors have no financial interest to declare in relation to the content of this article. Ethics Approval Statement: Written informed consent for sample collection was obtained from patients, and sample collection was approved by the Ethics Committee of Shanghai Ninth People’s Hospital (Shanghai, China).