MiR-126 Contributes to Human Umbilical Cord Blood Cell-Induced Neurorestorative Effects After Stroke in Type-2 Diabetic Mice.
MiR-126 Contributes to Human Umbilical Cord Blood Cell-Induced Neurorestorative Effects After Stroke in Type-2 Diabetic Mice.
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DOI：
10.1002/stem.2193
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发表时间：
2016-01
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影响因子：
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通讯作者：
Chopp M
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文献类型：
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作者：
Chen J;Ning R;Zacharek A;Cui C;Cui X;Yan T;Venkat P;Zhang Y;Chopp M
糖尿病（DM）是卒中的高危因素，与非糖尿病患者相比，糖尿病（DM）会导致更严重的血管和白质损伤。我们测试了延迟人脐带血细胞 (HUCBC) 治疗 2 型糖尿病 (T2DM) 中风的神经恢复效果。对db/db-T2DM和db/+-non-DM小鼠进行远端大脑中动脉闭塞(dMCAo)，并在dMCAo后3天用：1)non-DM+PBS； 2）T2DM+PBS； 3) T2DM + naïve-HUCBC； 4) T2DM + miR-126−/−HUCBC。在体内和体外测量功能评估、血管和白质变化、神经炎症和 miR-126 效应。与非糖尿病小鼠相比，T2DM 小鼠的血清和脑组织 miR-126 表达显着降低。 T2DM+HUCBC小鼠表现出miR-126表达增加、紧密连接蛋白表达增加、轴突/髓磷脂、血管密度和M2巨噬细胞极化增加；然而，与对照 T2DM 小鼠相比，HUCBC 治疗的 T2DM 小鼠的血脑屏障渗漏、脑出血、缺血脑中 miR-126 靶向基因 VCAM-1 和 MCP-1 的表达减少以及功能结果改善。 MiR-126−/−HUCBC 治疗消除了 T2DM 中风小鼠中未经处理的 HUCBC 治疗的益处。在体外，在原代培养的脑内皮细胞（BEC）中敲入 miR-126 或用 naïve-HUCBC 处理 BEC 显着增加毛细血管样管的形成，并增加原代培养的皮质神经元的轴突生长；而用 miR-126−/− HUCBC 处理 BEC 或皮质神经元会减弱 HUCBC 处理诱导的毛细管形成和轴突生长。我们的数据表明，延迟 HUCBC 治疗中风可增加血管/白质重塑和抗炎作用； MiR-126 可能有助于 HUCBC 诱导的 T2DM 小鼠神经恢复作用。
Diabetes mellitus (DM) is a high risk factor for stroke and leads to more severe vascular and white-matter injury than stroke in non-DM. We tested the neurorestorative effects of delayed human umbilical cord blood cell (HUCBC) treatment of stroke in type-2 diabetes (T2DM). db/db-T2DM and db/+-non-DM mice were subjected to distal middle cerebral artery occlusion (dMCAo) and were treated 3 days after dMCAo with: 1) non-DM + PBS; 2) T2DM + PBS; 3) T2DM + naïve-HUCBC; 4) T2DM + miR-126−/−HUCBC. Functional evaluation, vascular and white-matter changes, neuroinflammation, and miR-126 effects were measured in vivo and in vitro. T2DM mice exhibited significantly decreased serum and brain tissue miR-126 expression compared with non-DM mice. T2DM+HUCBC mice exhibited increased miR-126 expression, increased tight junction protein expression, axon/myelin, vascular density and M2-macrophage polarization; However, decreased blood-brain barrier leakage, brain hemorrhage and miR-126 targeted gene VCAM-1 and MCP-1 expression in the ischemic brain as well as improved functional outcome were present in HUCBC treated T2DM mice compare with control T2DM mice. MiR-126−/−HUCBC-treatment abolished the benefits of naïve-HUCBC-treatment in T2DM stroke mice. In vitro, knock-in of miR-126 in primary cultured brain endothelial cells (BECs) or treatment of BECs with naïve-HUCBCs significantly increased capillary-like tube formation, and increased axonal outgrowth in primary cultured cortical neurons; whereas treatment of BECs or cortical neurons with miR-126−/− HUCBC attenuated HUCBC-treatment induced capillary tube formation and axonal outgrowth. Our data suggest delayed HUCBC-treatment of stroke increases vascular/white-matter remodeling and anti-inflammatory effects; MiR-126 may contribute to HUCBC-induced neurorestorative effects in T2DM mice.