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Exosomes from miRNA-126-modified endothelial progenitor cells alleviate brain injury and promote functional recovery after stroke.

ABSTRACT: AIMS:We previously showed that the protective effects of endothelial progenitor cells (EPCs)-released exosomes (EPC-EXs) on endothelium in diabetes. However, whether EPC-EXs are protective in diabetic ischemic stroke is unknown. Here, we investigated the effects of EPC-EXs on diabetic stroke mice and tested whether miR-126 enriched EPC-EXs (EPC-EXsmiR126 ) have enhanced efficacy. METHODS:The db/db mice subjected to ischemic stroke were intravenously administrated with EPC-EXs 2 hours after ischemic stroke. The infarct volume, cerebral microvascular density (MVD), cerebral blood flow (CBF), neurological function, angiogenesis and neurogenesis, and levels of cleaved caspase-3, miR-126, and VEGFR2 were measured on day 2 and 14. RESULTS:We found that (a) injected EPC-EXs merged with brain endothelial cells, neurons, astrocytes, and microglia in the peri-infarct area; (b) EPC-EXsmiR126 were more effective than EPC-EXs in decreasing infarct size and increasing CBF and MVD, and in promoting angiogenesis and neurogenesis as well as neurological functional recovery; (c) These effects were accompanied with downregulated cleaved caspase-3 on day 2 and vascular endothelial growth factor receptor 2 (VEGFR2) upregulation till day 14. CONCLUSION:Our results indicate that enrichment of miR126 enhanced the therapeutic efficacy of EPC-EXs on diabetic ischemic stroke by attenuating acute injury and promoting neurological function recovery.

SUBMITTER: Wang J

PROVIDER: S-EPMC7702230 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Exosomes from miRNA-126-modified endothelial progenitor cells alleviate brain injury and promote functional recovery after stroke.

Wang Jinju J Chen Shuzhen S Zhang Wenfeng W Chen Yanfang Y Bihl Ji C JC

CNS neuroscience & therapeutics 20201003 12

<h4>Aims</h4>We previously showed that the protective effects of endothelial progenitor cells (EPCs)-released exosomes (EPC-EXs) on endothelium in diabetes. However, whether EPC-EXs are protective in diabetic ischemic stroke is unknown. Here, we investigated the effects of EPC-EXs on diabetic stroke mice and tested whether miR-126 enriched EPC-EXs (EPC-EXs<sup>miR126</sup> ) have enhanced efficacy.<h4>Methods</h4>The db/db mice subjected to ischemic stroke were intravenously administrated with E ...[more]

PMID: 33009888

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Project description:BackgroundMacrophage in the spinal cord injury (SCI) area imparts a chronic pro-inflammation effect that challenges the recovery of SCI. Previously, endothelial progenitor cell-produced exosomes (EPC-EXOs) have been noticed to facilitate revascularization and inflammation control after SCI. However, their effects on macrophage polarization remained unclear. This study aimed to investigate the EPC-EXOs' role in macrophage polarization and reveal its underlying mechanism.MethodsWe extracted the macrophages and EPC from the bone marrow suspension of C57BL/L mice by centrifugation. After cell identification, the EPC-EXOs were collected by ultra-high-speed centrifugation and exosome extraction kits and identified by transmission electron microscopy and nanoparticle tracking analysis. Then, macrophages were cultured with EPC-EXOs in different concentrations. We labeled the exosome to confirm its internalization by macrophage and detected the macrophage polarization marker level both in vitro and in vivo. We further estimated EPC-EXOs' protective effects on SCI by mice spinal cord tissue H&E staining and motor behavior evaluation. Finally, we performed RT-qPCR to identify the upregulated miRNA in EPC-EXOs and manipulate its expression to estimate its role in macrophage polarization, SOCS3/JAK2/STAT3 pathway activation, and motor behavior improvement.ResultsWe found that EPC-EXOs decreased the macrophages' pro-inflammatory marker expression and increased their anti-inflammatory marker expression on the 7 and 14 days after SCI. The spinal cord H&E staining results showed that EPC-EXOs raised the tissue-sparing area rate significantly after 28 days of SCI and the motor behavior evaluation indicated an increased BMS score and motor-evoked potential by EPC-EXOs treatment after SCI. The RT-qPCR assay identified that miR-222-3P upregulated in EPC-EXOs and its miRNA-mimic also decreased the pro-inflammatory macrophages and increased the anti-inflammatory macrophages. Additionally, miR-222-3P mimic activated the SOCS3/JAK2/STAT3 pathway, and SOCS3/JAK2/STAT3 pathway inhibition blocked miR-2223P's effects on macrophage polarization and mouse motor behavior.ConclusionComprehensively, we discovered that EPC-EXOs-derived miR-222-3p affected macrophage polarization via SOCS3/JAK2/STAT3 pathway and promoted mouse functional repair after SCI, which reveals EPC-EXOs' role in modulation of macrophage phenotype and will provide a novel interventional strategy to induce post-SCI recovery.

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Exosomes from miRNA-126-modified endothelial progenitor cells alleviate brain injury and promote functional recovery after stroke.

Publications

Exosomes from miRNA-126-modified endothelial progenitor cells alleviate brain injury and promote functional recovery after stroke.

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