Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection

Apoptotic endothelial cells release microRNA-containing microvesicles to modulate the responses of neighboring cells and reduce atherosclerosis in mice. Sounding the Alarm In addition to its importance in development and homeostasis, apoptotic cell death is implicated in a number of diseases, including atherosclerosis. Apoptotic endothelial cells at atherosclerotic plaques release microvesicles known as apoptotic bodies into the circulation, and their abundance correlates with negative indicators of disease. Zernecke et al. showed that apoptotic bodies from endothelial cells contained microRNA-126 (miR-126). Neighboring vascular cells took up the microvesicles, which allowed miR-126 to reduce the abundance of an inhibitor of the signaling of the chemokine receptor CXCR4, resulting in the increased production of CXCL12, the ligand for CXCR4. CXCL12 mediated the recruitment to atherosclerotic plaques of progenitor cells from the bone marrow, which limited plaque size. Apoptotic bodies isolated from human patients with atherosclerosis reduced the size of plaques in different mouse models of atherosclerosis. Thus, dying endothelial cells send alarm signals in the form of packaged microRNA to neighboring cells to trigger a healing response that reduces atherosclerosis. Apoptosis is a pivotal process in embryogenesis and postnatal cell homeostasis and involves the shedding of membranous microvesicles termed apoptotic bodies. In response to tissue damage, the CXC chemokine CXCL12 and its receptor CXCR4 counteract apoptosis and recruit progenitor cells. Here, we show that endothelial cell–derived apoptotic bodies are generated during atherosclerosis and convey paracrine alarm signals to recipient vascular cells that trigger the production of CXCL12. CXCL12 production was mediated by microRNA-126 (miR-126), which was enriched in apoptotic bodies and repressed the function of regulator of G protein (heterotrimeric guanosine triphosphate–binding protein) signaling 16, an inhibitor of G protein–coupled receptor (GPCR) signaling. This enabled CXCR4, a GPCR, to trigger an autoregulatory feedback loop that increased the production of CXCL12. Administration of apoptotic bodies or miR-126 limited atherosclerosis, promoted the incorporation of Sca-1+ progenitor cells, and conferred features of plaque stability on different mouse models of atherosclerosis. This study highlights functions of microRNAs in health and disease that may extend to the recruitment of progenitor cells during other forms of tissue repair or homeostasis.