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

被引:1097
作者
Zernecke, Alma [1 ,2 ]
Bidzhekov, Kiril [1 ]
Noels, Heidi [1 ]
Shagdarsuren, Erdenechimeg [1 ]
Gan, Lin [3 ]
Denecke, Bernd [3 ]
Hristov, Mihail [1 ]
Koeppel, Thomas
Jahantigh, Maliheh Nazari [1 ]
Lutgens, Esther [1 ,4 ]
Wang, Shusheng [5 ]
Olson, Eric N. [5 ]
Schober, Andreas [1 ]
Weber, Christian [1 ,4 ]
机构
[1] Rhein Westfal TH Aachen, IMCAR, D-52074 Aachen, Germany
[2] Univ Wurzburg, DFG Res Ctr Expt Biomed, Rudolf Virchow Ctr, D-97080 Wurzburg, Germany
[3] Rhein Westfal TH Aachen, Dept Vasc Surg, Interdisciplinary Ctr Clin Res BIOMAT, D-52074 Aachen, Germany
[4] Univ Maastricht, CARIM, NL-6200 MD Maastricht, Netherlands
[5] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA
关键词
SMOOTH-MUSCLE-CELLS; PROGENITOR CELLS; HORIZONTAL TRANSFER; NEOINTIMA FORMATION; ENDOTHELIAL-CELLS; STEM-CELLS; ATHEROSCLEROSIS; MICROPARTICLES; ANGIOGENESIS; INFLAMMATION;
D O I
10.1126/scisignal.2000610
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:11
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