Histone Deacetylase 7-Derived 7-Amino Acid Peptide Increases Skin Wound Healing via Regulating Epidermal Fibroblast Proliferation and Migration

Abstract

Due to the complexity of wound healing, how to achieve successful healing is a significant clinical challenge. In this study, we found that the histone deacetylase-7-derived 7-amino acid peptide (7A, MHSPGAD), especially its phosphorylated version 7Ap (MH[pSer]PGAD), increased dermal fibroblast cell HDFα proliferation and migration via elevated delta-catenin (CTNND1) serine phosphorylation-mediated beta-catenin (CTNNB) nuclear translocation and subsequent upregulation of c-Myc and cyclin D1 expression. 7Ap physically interacted with platelet-derived growth factor receptor (PDGFR) and increased PDGFR interaction with cyclin-dependent kinase 6 (CDK6). The PDGFR siRNA or CDK6 siRNA knockdown ablated 7AP-induced CTNND1 phosphorylation and subsequent c-Myc/cyclin D1 expression, indicating a novel 7Ap-PDGFR-CDK6-CTNND1/CTNNB signal pathway in regulating fibroblast proliferation and migration. Furthermore, 7Ap increased human umbilic vein endothelial cell proliferation and tube formation, suggesting an angiogenic effect. In a full-thickness excision wound rat model, the local administration of 50 ng/mL of 7Ap in hydrogel exerted a similar effect as 1 μg/mL vascular endothelial growth factor on accelerating wound healing, featured by enhanced fibroblast proliferation and migration, collagen deposition, and increased new vessel formation during the early phase of wound healing. Taken together, this study not only elicited a novel signal pathway in fibroblast proliferation but also paved an avenue to develop 7Ap as a treatment option for skin wound healing.