MicroRNA-146a Induces Lineage-Negative Bone Marrow Cell Apoptosis and Senescence by Targeting Polo-Like Kinase 2 Expression

Objective— Lineage-negative bone marrow cells (lin− BMCs) are enriched in endothelial progenitor cells and mediate vascular repair. Aging-associated senescence and apoptosis result in reduced number and functionality of lin− BMCs, impairing their prorepair capacity. The molecular mechanisms underlying lin− BMC senescence and apoptosis are poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin− BMCs is a critical step in understanding the process of vascular repair. The aim of this study was to characterize the role of the miR-146a–Polo-like kinase 2 (Plk2) network in regulating lin− BMC senescence, apoptosis, and their angiogenic capability. Approach and Results— Transcriptome analysis in lin− BMCs isolated from young and aged wild-type and ApoE −/− (apolipoprotein E) mice showed a significant age-associated increase in miR-146a expression. In silico analysis, expression study and Luciferase reporter assay established Plk2 as a direct target of miR-146a. miR-146a overexpression in young lin− BMCs inhibited Plk2 expression, resulting in increased senescence and apoptosis, via p16Ink4a/p19Arf and p53, respectively, as well as impaired angiogenic capacity in vitro and in vivo. Conversely, suppression of miR-146a in aged lin− BMCs increased Plk2 expression and rejuvenated lin− BMCs, resulting in decreased senescence and apoptosis, leading to improved angiogenesis. Conclusions— (1) miR-146a regulates lin− BMC senescence and apoptosis by suppressing Plk2 expression that, in turn, activates p16Ink4a/p19Arf and p53 and (2) modulation of miR-146a or its target Plk2 may represent a potential therapeutic intervention to improve lin− BMC–mediated angiogenesis and vascular repair.