Endothelin-1 augments the therapeutic potency of human mesenchymal stem cells via GATA2 and MZF1 mediated N-cadherin-VEGF axis

Abstract

In the previous paper, we reported that individual difference of hUCB-MSCs and N-cadherin as a significant marker on therapeutic efficacy of rat myocardial infarction.1 We performed cDNA microarray analysis with the best and the worst efficacy-representing hUCB-MSCs to identify critical factor which induces augmentation of therapeutic efficacy. In this study, among of several factors, we focused on Endothelin-1(ET-1). Interestingly, it has been reported that ET-1 is increased in myocardial infarction and high ET-1 levels are related with microvascular dysfunction and lower salvage index.2 So, there have been many studies that concentrated to the blocking of ET-1 pathway via endothelin receptor antagonist or neutralization.3-7 However, ET-1 was high expressed in the best efficacy-representing hUCB-MSCs and lower in counterpart. To validate the potency of ET-1 as a priming factor, we detected the N-cadherin-VEGF axis after ET-1 treatment. Both N-cadherin and VEGF mRNA and protein expression levels were up-regulated by ET-1 priming event. We also verified that hUCB-MSCs are expressing the endothelin receptor type A not B and ET-1 up-regulates the N-cadherin-VEGF axis via endothelin receptor type A. Then, to screen N-cadherin transcriptional activator depended on ET-1, we searched N-cadherin promoter region and developed GATA2 and MZF1. Finally, to validate therapeutic efficacy of ET-1 priming, we injected ET-1 primed hUCB-MSCs to rat myocardial infarction model and obtained the outcomes that the ET-1 pre-treated hUCB-MSCs improved the therapeutic efficacy in rat myocardial infarction than non-treated hUCB-MSCs. Histological analysis also showed that increased engraftment efficacy and reduced fibrosis area on the ET-1 pre-treated hUCB-MSCs.