Abstract
Endothelial colony forming cell (ECFC)-derived exosomes protect mice against ischemic kidney injury, via transfer of microRNA-(miR)-486-5p. Mechanisms mediating exosome recruitment to tissues are unclear. We hypothesized that ECFC exosomes target ischemic kidneys, involving interaction between exosomal CXC chemokine receptor type 4 (CXCR4) and stromal cell-derived factor (SDF)-1α. Ischemia-reperfusion was induced in mice by bilateral renal vascular clamp, with intravenous infusion of exosomes at reperfusion. Optical imaging determined exosome biodistribution, and miR-486-5p was measured by real-time PCR. Human umbilical vein endothelial cells (HUVECs) were cultured to study the CXCR4/SDF-1α interaction. Targeting of administered exosomes to ischemic kidneys was detected 30 min and 4 hrs after reperfusion. Exosomes increased miR-486-5p levels only in kidneys, within proximal tubules, glomeruli, and endothelial cells. Uptake of fluorescently-labeled exosomes into HUVECs, and exosomal transfer of miR-486-5p were enhanced by hypoxia, effects blocked by neutralizing antibody to SDF-1α or by the CXCR4 inhibitor plerixafor. Infusion of ECFC exosomes prevented ischemic kidney injury in vivo, an effect that was not observed when exosomes were pre-incubated with plerixafor. These data indicate that ECFC exosomes selectively target the kidneys after ischemic injury, with rapid cellular transfer of miR486-5p. Targeting of exosomes may involve interaction of CXCR4 with endothelial cell SDF-1α.
Highlights
Graph depicts size distributions of unlabeled exosomes, as well as exosomes labeled with dioctadecyltetramethyl indotricarbocyanine iodide (DiR) or PKH26, isolated from Endothelial colony forming cell (ECFC) conditioned medium, by nanoparticle tracking analysis
In a mouse model of kidney ischemia, we demonstrated that intravenous infusion of exosomes derived from human cord blood endothelial colony forming cells (ECFCs) reduced kidney ischemic injury, associated with decreased histologic damage, apoptosis, and neutrophil infiltrate[14]
In mice with ischemia/reperfusion kidney injury treated with DiR-labeled exosomes at the time of reperfusion, fluorescence was enhanced in the region around the kidneys at 30 min, compared to sham mice treated with DiR-labeled exosomes (Fig. 2a)
Summary
Graph depicts size distributions of unlabeled exosomes, as well as exosomes labeled with DiR or PKH26, isolated from ECFC conditioned medium, by nanoparticle tracking analysis. Cells within injured tissues has not been consistently demonstrated, and the protective effects of EPCs have been attributed to paracrine mechanisms In this regard, extracellular vesicles have emerged as leading candidates mediating the protective effects of EPCs in models of ischemic tissue injury. In a mouse model of kidney ischemia, we demonstrated that intravenous infusion of exosomes derived from human cord blood endothelial colony forming cells (ECFCs) reduced kidney ischemic injury, associated with decreased histologic damage, apoptosis, and neutrophil infiltrate[14]. Infusion of ECFC exosomes at the time of reperfusion in mice with kidney ischemia was associated with an increase in kidney levels of miR-486-5p after 24 hrs, suggesting transfer of miR-486-5p to the injured kidney. We tested the hypothesis that infused ECFC exosomes target the kidneys in mice with ischemia/reperfusion injury, leading to selective transfer of miR-486-5p. We studied the potential role of exosomal CXCR4 and SDF-1α in mediating selective targeting of exosomes in ischemic injury
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