Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
Department of Biomedical Science, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
CNS Neurosci Ther. 2020 Dec;26(12):1255-1265. doi: 10.1111/cns.13455. Epub 2020 Oct 3.
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 ) have enhanced efficacy.
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.
We found that (a) injected EPC-EXs merged with brain endothelial cells, neurons, astrocytes, and microglia in the peri-infarct area; (b) EPC-EXs 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.
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.
我们之前的研究表明，内皮祖细胞（EPC）释放的外泌体（EPC-EXs）对糖尿病中的内皮具有保护作用。然而，EPC-EXs 在糖尿病性缺血性中风中是否具有保护作用尚不清楚。在这里，我们研究了 EPC-EXs 对糖尿病性中风小鼠的影响，并测试了富含 miR-126 的 EPC-EXs（EPC-EXs）是否具有增强的疗效。
在缺血性中风后 2 小时，将 db/db 小鼠静脉内给予 EPC-EXs。在第 2 天和第 14 天，测量梗死体积、脑微血管密度（MVD）、脑血流量（CBF）、神经功能、血管生成和神经发生以及半胱天冬酶-3 切割、miR-126 和血管内皮生长因子受体 2（VEGFR2）的水平。
我们发现：（a）注射的 EPC-EXs 在梗死周围区域与脑内皮细胞、神经元、星形胶质细胞和小胶质细胞融合；（b）EPC-EXs 比 EPC-EXs 更有效地减少梗死体积，增加 CBF 和 MVD，并促进血管生成和神经发生以及神经功能恢复；（c）这些作用伴随着第 2 天 cleaved caspase-3 的下调和第 14 天血管内皮生长因子受体 2（VEGFR2）的上调。
我们的结果表明，miR126 的富集通过减轻急性损伤和促进神经功能恢复，增强了 EPC-EXs 对糖尿病性缺血性中风的治疗效果。
