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

• Published in: Stem cells translational medicine Vol. 4; no. 5; pp. 513 - 522
• Main Authors: Zhang, Bin, Wu, Xiaodan, Zhang, Xu, Sun, Yaoxiang, Yan, Yongmin, Shi, Hui, Zhu, Yanhua, Wu, Lijun, Pan, Zhaoji, Zhu, Wei, Qian, Hui, Xu, Wenrong
• Format: Journal Article
• Language: English
• Published: Durham, NC, USA AlphaMed Press 01.05.2015; Oxford University Press
• Subjects: Angiogenesis; Animals; beta Catenin - biosynthesis; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Burns; Catenin; Cell activation; Cell proliferation; Cyclin D3; Data analysis; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - transplantation; Exosomes; Exosomes - metabolism; Exosomes - transplantation; Gene Expression Regulation - drug effects; Grants; Humans; Mesenchymal Stromal Cells - cytology; Mesenchyme; Neovascularization, Physiologic; Nuclear transport; Proliferating cell nuclear antigen; Proteins; Pyrimidinones - administration & dosage; Rats; Regeneration; Regenerative medicine; Signal Transduction - drug effects; Skin; Stem cell transplantation; Stem cells; Tissue engineering; Tissue Engineering and Regenerative Medicine; Transmission electron microscopy; Umbilical cord; Umbilical Cord - cytology; Wnt protein; Wnt4; Wnt4 Protein - biosynthesis; Wound Healing; β-Catenin; China; Angiogenesis; β-Catenin; Exosomes; Regenerative medicine; Wnt4
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2014-0267

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. 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 not well understood. The results of this study suggest that hucMSC‐exosome‐mediated Wnt4 induces β‐catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing.