Abstract 19145: Modulation of MicroRNA-126 Expression Leads to Marked Changes in the Pro-angiogenic Capacity of Autologous Human CD34+ Stem/Progenitor Cells
Circulating, BM derived CD34+ progenitor cells have been suggested to contribute importantly to neovascularisation and vascular repair. Administration of these cells is explored as a potential novel therapy to improve cardiac perfusion and function. Notably CD34+ cells represent a heterogeneous cell population; moreover, recently differential microRNA (miR) expression has been suggested to regulate the phenotype of CD34+ cell subsets. We therefore characterized the angiogenic capacity and endothelial repair effects of freshly isolated subsets of circulating mononuclear cells, in particular CD34+/14+, CD34+/14-, CD14+CD34- (monocytes) and CD14-CD34-(lymphocytes). CD34+ cells (CD34+/14+ and CD34+/14- cells) exerted pro angiogenic effect on endothelial cells (promotion of tube formation), that was not observed inCD34- cell fractions. To understand mechanisms leading to differential pro angiogenic stimulation we performed RT-PCR miR array. 10 miRs were identified to be markedly differentially expressed in CD34+ cells as compared to CD34- cells, of which miR 126 was the most prominent. Moreover, transfection with anti-miR 126 resulted in significant reduction of tube formation whereas miR 126 mimic significantly increased tube formation capacity of CD34+ cells, suggesting that pro angiogenic effects of circulating CD34+ progenitor cells are dependent on the pro angiogenic miR-126 expression, and can be further enhanced by increasing expression of this miR in CD34+ cells. Further mechanistic studies showed SPRED-1 and VEGF-A, direct targets of miR 126, are involved in the modulation of the pro angiogenic capacities of CD34+ cells. In addition, to further determine the miR 126 regulation in CD34+ cells, these cells were treated with high glucose for 4–7 days. This resulted in a marked down regulation of miR 126 expression by 3 fold, paralled by a loss of their pro angiogenic capacity.
Conclusions: The present findings suggest that pro angiogenic capacity of CD34+ cells is critically dependent on miR 126 expression. Furthermore, miR 126 is markedly down-regulated by high glucose, associated with loss of pro angiogenic capacity of CD34+ cells. By modulating expression of miR 126, pro angiogenic capacity of CD34+ cells can be markedly stimulated.
- © 2010 by American Heart Association, Inc.