Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
Institute of Microsurgery and Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
Stem Cell Res Ther. 2020 Jul 22;11(1):313. doi: 10.1186/s13287-020-01834-0.
Small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSC) derived from human induced pluripotent stem cells (iPSC, iMSC-sEV) are considered to have great potential in treating ischemic diseases. Angiogenesis play an important role in post-stroke recovery. However, no studies have yet been conducted to systemically examine the effect and the underlying mechanism of iMSC-sEV on angiogenesis under brain ischemia conditions.
Ischemic stroke model was performed in rats induced by middle cerebral artery occlusion (MCAO), and the pro-angiogenic capacity of iMSC-sEV was measured. The in vitro effects of iMSC-sEV on the migration and tube formation of endothelial cells were investigated, respectively. Autophagy and autophagy-related signaling pathway were detected in vivo and in vitro.
We found that iMSC-sEV significantly reduced infarct volume, enhanced angiogenesis, and alleviated long-term neurological deficits in rats after stroke. We also demonstrated that iMSC-sEV increased migration and tube formation of endothelial cells in vitro. A further mechanism study revealed that the pro-angiogenic effect of iMSC-sEV was correlated with a reduction in autophagy. Furthermore, iMSC-sEV significantly activated signal transducer and activator of transcription 3 (STAT3), and suppression of STAT3 abolished iMSC-sEV-induced inhibition of autophagy and promotion of angiogenesis in vivo and in vitro.
Taken together, our data indicate that iMSC-sEV promote angiogenesis after ischemic stroke, potentially, by inhibiting autophagy, a process that is partially dependent on STAT3 activation.
来源于人诱导多能干细胞（iPSC）的间充质干细胞（MSC）分泌的小细胞外囊泡（sEV）被认为在治疗缺血性疾病方面具有巨大潜力。血管生成在中风后恢复中起着重要作用。然而，目前还没有研究系统地检查 iMSC-sEV 在脑缺血条件下对血管生成的作用及其潜在机制。
通过大脑中动脉闭塞（MCAO）诱导大鼠缺血性中风模型，测量 iMSC-sEV 的促血管生成能力。分别研究了 iMSC-sEV 对内皮细胞迁移和管形成的体外作用。在体内和体外检测自噬和自噬相关信号通路。
我们发现 iMSC-sEV 可显著减少大鼠中风后的梗死体积、增强血管生成并减轻长期神经功能缺损。我们还证明了 iMSC-sEV 可增加内皮细胞的迁移和管形成。进一步的机制研究表明，iMSC-sEV 的促血管生成作用与自噬减少有关。此外，iMSC-sEV 可显著激活信号转导子和转录激活子 3（STAT3），抑制 STAT3 可消除 iMSC-sEV 诱导的自噬抑制和体内及体外血管生成促进作用。
总之，我们的数据表明 iMSC-sEV 通过抑制自噬促进缺血性中风后的血管生成，这一过程部分依赖于 STAT3 的激活。
