Morroniside promotes skin wound re-epithelialization by facilitating epidermal stem cell proliferation through GLP-1R-mediated upregulation of β-catenin expression.

Abstract

Epidermal stem cells (EpSCs) play a vital role in skin wound healing through re-epithelialization. Identifying chemicals that can promote EpSC proliferation is helpful for treating skin wounds. This study investigates the effect of morroniside on cutaneous wound healing in mice and explores the underlying mechanisms. Application of 10‒50 μg/mL of morroniside to the skin wound promotes wound healing in mice. In vitro studies demonstrate that morroniside stimulates the proliferation of mouse and human EpSCs in a time- and dose-dependent manner. Mechanistic studies reveal that morroniside promotes the proliferation of EpSCs by facilitating the cell cycle transition from the G1 to S phase. Morroniside increases the expression of β-catenin via the glucagon-like peptide-1 receptor (GLP-1R)-mediated PKA, PKA/PI3K/AKT and PKA/ERK signaling pathways, resulting in an increase in cyclin D1 and cyclin E1 expression, either directly or by upregulating c-Myc expression. This process ultimately leads to EpSC proliferation. Administration of morroniside to mouse skin wounds increases the phosphorylation of AKT and ERK, the expressions of β-catenin, c-Myc, cyclin D1, and cyclin E1, as well as the proliferation of EpSCs, in periwound skin tissue, and accelerates wound re-epithelialization. These effects of morroniside are mediated by the GLP-1R. Overall, these results indicate that morroniside promotes skin wound healing by stimulating the proliferation of EpSCs via increasing β-catenin expression and subsequently upregulating c-Myc, cyclin D1, and cyclin E1 expressions through GLP-1R signaling pathways. Morroniside has clinical potential for treating skin wounds.