Receptor-Ligand Interaction Mediates Targeting of Endothelial Colony Forming Cell-derived Exosomes to the Kidney after Ischemic Injury

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.

Advances in Analysis of Biodistribution of Exosomes by Molecular Imaging

“…Since MSCs are known to accumulate in damaged tissues through the interactions of receptors on the MSCs and target tissues [109,110], it is highly probable that MSC-exosomes are also localized in damaged tissues due to these receptor interactions. Similarly, exosomes from endothelial progenitor cells showed accumulation in ischemic kidney to prevent ischemic injury through CXCR4-SDF-1α interaction [91].…”

A Novel Approach to Deliver Therapeutic Extracellular Vesicles Directly into the Mouse Kidney via Its Arterial Blood Supply

“…In the brain, in vivo neuroimaging of gold-labeled EVs has shown that EVs home to areas of brain pathologies in mice, but distribute diffusely in uninjured brains [33,34]. One study has shown that human umbilical vein endothelial cell (HUVEC)-derived EVs home to ischemic kidneys, but not uninjured kidneys, for at least 4 h post-injection, an effect likely mediated by CXCR4/SDF-1α interactions [35]. Even less studied are methods to further optimize EV homing to specific target tissues.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics and as a Drug Delivery Platform

“…Mostly homes to the liver and spleen, and surface engineering of exosomes can induce targeting ability …”

“…Similarly, He et al showed protection against kidney damage in the subtotal nephrectomy murine model of renal regeneration by decreasing the levels of uric acid, creathinine, fibrosis, and lymphocyte infiltration by treating MSC-derived EVs [31]. In another murine [29,30] Retains therapeutic effects of MSCs, and loading therapeutic cargo can increase their effects [2,5,25,31,32] Homing to target tissue Home to sites of injury and cancer, but less than 1% of MSCs result in engraftment [33] Mostly homes to the liver and spleen, and surface engineering of exosomes can induce targeting ability [34][35][36] Can pass though the blood-brain barrier [37] Rejection Can induce allogenic immune rejection [38,39] Considered to be nonimmunogenic [41]. Furthermore, the therapeutic potential of MSCderived EVs was also verified in a murine model of fibrotic liver induced by carbon tetrachloride [5] and in a rat skin burn model [42].…”