Abstract 16509: Microrna-126 is Released in Microvesicles From Cd34+ Progenitor Cells and is Critical for Their Pro-Angiogenic Capacity - Down-Regulation in Diabetes
Bone-marrow derived, circulating CD34+ progenitor cells have been observed to promote cardiac neovascularisation and vascular repair. Recently, microRNAs (miR) have emerged as key regulators of the angiogenesis. In the present study we have characterized angiogenic capacity of freshly isolated subsets of mononuclear cells, in particular CD34+/14+, CD34+/14-, CD14+CD34- (monocytes) and CD14-CD34- (lymphocytes) and their miR expression profile using an RT-PCR microRNA array. CD34+ fractions (CD34+/14+, CD34+/14- ) promoted tube-formation in endothelial cells significantly higher than CD34- fractions. Moreover, supernatants of CD34+ cells exerted substantial pro-angiogenic stimulation. 10 miRs were identified to be differentially expressed in CD34+ cells as compared to CD34- cells, of which miR-126 was the most prominent. Assessing of miR-126 levels in conditioned medium revealed significantly higher levels of miR-126 in CD34+ cell as compared to CD34- fractions, with no significant difference between the CD34+/14+, CD34+/14- cells. Further, miR-126 is mostly present in microvesicles and to a lesser extent in exosomes. Further, expression of miR-126 in CD34+ cells under diabetic conditions was reduced in CD34+ cells as compared to CD34+ cells from healthy subjects. Notably, loss of pro-angiogenic capacity in high glucose treated CD34+ cells was restored by increasing levels of miR-126 using miRmimic-126. Moreover, miRmimic-126, but not scrambled (scr) miR, increased tube formation capacity of high glucose treated ECs. In-vivo matrigel plug assay in diabetic mice (streptozotocin induced) revealed higher capillary density in mice receiving miRmimic-126 than mice receiving matrigel containing scr miR.
Conclusions: These findings suggest that, pro-angiogenic capacity of CD34+ cells is critically dependent on miR-126 expression, and that miR-126 is secreted in particular in microvesicles. Reduced levels of miR-126 represents a novel mechanism contributing to impaired pro-angiogenic capacity in diabetic CD34+ cells. By increasing miR-126 levels in diabetic CD34+ cells pro-angiogenic capacity could be markedly stimulated, providing a novel opportunity for optimisation of cell-based treatment approaches in these patients.
- © 2011 by American Heart Association, Inc.