Human Umbilical Cord-Derived Mesenchymal Stem Cells Relieve Hind Limb Ischemia by Promoting Angiogenesis in Mice

Chronic critical limb ischemia (CLI) represents a clinical end stage of peripheral arterial disease. Many CLI patients are ineligible for conventional revascularization therapies; thus, it is urgent to explore an alternative strategy to rescue the ischemic limb. Recent stem cell studies have greatly developed the field of therapeutic angiogenesis, which aims to significantly improve the limb blood supply. In our study, bone marrow mesenchymal stem cells (BMMSCs) served as the control to evaluate the function of umbilical cord mesenchymal stem cells (UCMSCs) in enhancing angiogenesis. We compared gene expression between BMMSCs and UCMSCs, and a bioinformatics analysis indicated that both UCMSCs and BMMSCs could stimulate angiogenesis and angiogenesis-related factors were upregulated in UCMSCs. In vitro assays indicated that both BMMSCs and UCMSCs promoted human umbilical vein endothelial cell proliferation, migration, and tube formation, and the effects of UCMSCs were more obvious. Consistent with in vitro results, both UCMSCs and BMMSCs improved the limb blood supply in a mouse model of hind limb ischemia, in which UCMSCs promoted angiogenesis more significantly. Finally, we found that activation of ERK and PI3K-Akt pathways might be the mechanism by which UCMSCs promote angiogenesis. These results indicate that UCMSCs play an important role in therapeutic angiogenesis to improve limb blood perfusion.