Abstract 11312: MicroRNA-29 and MicroRNA-126 Work in Tandem to Decrease the Differentiation and Angiogenic Capability of Aging Bone Marrow-Derived Endothelial Progenitor Cells
Background: Bone marrow (BM) lineage negative fraction (lin- BMCs) enriched for mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), appear to mediate cardiac repair via direct differentiation into cardiomyocytes, paracrine effects and promoting angiogenesis. Lin- BMC/EPC senescence may adversely affect the therapeutic efficacy of autologous BM cell therapy. MicroRNAs (miRNA) act as critical modulators for cellular and organismal aging. The Aim of this study was to determine whether miRNA regulated age-related senescence and functionality in cardiac repair of lin- BMCs.
Methods: Lin- BMCs/EPCs were isolated from young and old wild type (WT) and apoE-/- mice. Genome-wide miRNA and gene expression profiling was analyzed. Genetic modulation and in vitro and in vivo angiogenesis assays were performed.
Results: MiRNA and gene expression profiling revealed differential expression changes of miR-29c, Klf2a, miR-126 and spred-1 in young and old EPCs. Specifically, miR-29c was increased and miR-126a was decreased in old EPCs, whereas their target genes Klf2a and Spred-1 showed opposite changes, relative to their young counterparts, respectively. Overexpression of miR-29c in young EPCs caused decreased Klf2 and miR-126 expression and increased Spred1 expression, resulting in decreased VEGF signaling and diminished vascular tube formation. Conversely, inhibition of miR-29c expression increased Klf2 and miR126a expression leading to enhanced VEGF signaling and vascular tube formation. Furthermore, intra-myocardial injection of old EPCs genetically modified with miR-29c antagomir or miR-126a significantly increased neovascularization in ischemic tissues, markedly reduced infarct size and improved cardiac function in a mouse acute myocardial infarct model.
Conclusions: We have discovered that the miR-29c-↓Klf2a-↓miR-126-↑Spred-1-↓VEGF signaling pathway regulates EPC differentiation in the context of aging. These findings may provide molecular targets for genetic modification to enhance the efficacy of BM-based cardiac repair.
- © 2013 by American Heart Association, Inc.