Human Umbilical Cord Mesenchymal Stem Cell Exosomes Enhance Angiogenesis Through the Wnt4/β-Catenin Pathway

TLDR

Human umbilical cord mesenchymal stem cells and their exosomes are promising regenerative therapeutics, yet the mechanisms underlying their effects remain unclear. The study isolated and characterized hucMSC‑derived exosomes and examined their dose‑dependent promotion of endothelial cell proliferation, migration, and tube formation. hucMSC‑derived exosomes enhance endothelial proliferation, migration, tube formation, and cutaneous wound healing by delivering Wnt4, which activates β‑catenin signaling; this effect is dose‑dependent, reversible by β‑catenin inhibition, and abrogated when Wnt4 is knocked down.

Abstract

Abstract Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, we isolated and characterized the exosomes from hucMSCs (hucMSC-Ex) and demonstrated that hucMSC-Ex promoted the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Furthermore, we demonstrated that hucMSC-Ex promoted wound healing and angiogenesis in vivo by using a rat skin burn model. We discovered that hucMSC-Ex promoted β-catenin nuclear translocation and induced the increased expression of proliferating cell nuclear antigen, cyclin D3, N-cadherin, and β-catenin and the decreased expression of E-cadherin. The activation of Wnt/β-catenin is critical in the induction of angiogenesis by hucMSC-Ex, which could be reversed by β-catenin inhibitor ICG-001. Wnt4 was delivered by hucMSC-Ex, and the knockdown of Wnt4 in hucMSC-Ex abrogated β-catenin nuclear translocation in endothelial cells. The in vivo proangiogenic effects were also inhibited by interference of Wnt4 expression in hucMSC-Ex. Taken together, these results suggest that hucMSC-Ex-mediated Wnt4 induces β-catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing. Significance Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, it is reported that hucMSC-Ex-mediated Wnt4 induces β-catenin activation in endothelial cells and exerts proangiogenic effects, which could be one of the important mechanisms responsible for cutaneous wound healing.