Endothelin-1 Augments Therapeutic Potency of Human Mesenchymal Stem Cells via CDH2 and VEGF Signaling

摘要

In our previous study, we identified differences in the levels ofCDH2 and vascular endothelial growth factor (VEGF) betweeneffective and ineffective clones of human umbilical cord blood(hUCB) mesenchymal stem cells (MSCs), with regard to theinfarcted rat myocardium. In this study, we compared geneexpression profiles between the effective and ineffective clonesand identified that endothelin-1 (EDN1) is enriched in theeffective clone. In the mechanistic analyses, EDN1 significantlyincreased expression of CDH2 and VEGF through endothelinreceptor A (EDNRA), which was prevented by EDNRA blocker,BQ123. To decipher how EDN1 induced gene expression ofCDH2, we performed a promoter activity assay and identifiedGATA2 and MZF1 as inducers of CDH2. EDN1 significantlyenhanced the promoter activity of the CDH2 gene, which wasobliterated by the deletion or point mutation at GATA2 orMZF1 binding sequence. Next, therapeutic efficacy of EDN1-priming of hUCB-MSCs was tested in a rat myocardial infarction(MI) model. EDN1-primed MSCs were superior to naiveMSCs at 8 weeks after MI in improving myocardial contractility(p 0.05), reducing fibrosis area (p 0.05), increasingengraftment efficiency (p 0.05), and improving capillary density(p 0.05). In conclusion, EDN1 induces CDH2 and VEGFexpression in hUCB-MSCs, leading to the improved therapeuticefficacy in rat MI, suggesting that EDN1 is a potential primingagent for MSCs in regenerative medicine.