Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke.
Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke.
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DOI：
10.18632/oncotarget.12902
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发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Yip HK
中科院分区：
文献类型：
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作者：
Chen KH;Chen CH;Wallace CG;Yuen CM;Kao GS;Chen YL;Shao PL;Chen YL;Chai HT;Lin KC;Liu CF;Chang HW;Lee MS;Yip HK
我们验证了脂肪来源的异种间充质干细胞(ADMSC)和ADMSC来源的外切体联合治疗能减少脑梗死区(BIZ)和促进神经功能恢复的假说。成年雄性SD大鼠60只，随机分为假手术对照组(Sham-Control)、假手术组(AIS)、AIS-ADMSC组、AIS-Exosome(100μg)组和AIS-Exosome-ADMSC组。所有治疗均于AIS术后3h静脉注射。组织病理学(60天)和脑核磁共振(28天)测定的BIZ在第2组最高，第1组最低，第3组和第4组高于第5组，但第3组和第4组之间没有差异(P均<0.0001)。到第28天，五组患者的感觉运动功能结果显示出与BIZ相反的模式(p<；0.005)。炎症性(诱导型一氧化氮合酶/肿瘤坏死因子-α/核因子-κB/白介素1-β/基质金属蛋白酶-9/纤溶酶原激活物抑制物-1/RANTES)、氧化应激(NOX-1/NOX-2/氧化蛋白)、凋亡(caspase-3/聚-腺苷二磷酸核糖聚合酶)和纤维化(Smad3/转化生长因子-β)生物标志物的蛋白表达，以及脑损伤细胞表达(γ-H_2AX+/XRCC1-CD90+/p53BP1-CD90+)，炎症(CD11+/CD68+/胶质纤维酸性蛋白+)和脑水肿(水通道蛋白-4+)标记物在各组之间显示出相似的BIZ模式(所有n<；0.0001)。综上所述，异种ADMSC/ADMSC来源的外切体治疗是安全的，并提供了减少BIZ和改善大鼠AIS神经功能的额外好处。
We tested the hypothesis that combined xenogenic (from mini-pig) adipose-derived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) and enhance neurological recovery in rat after acute ischemic stroke (AIS) induced by 50-min left middle cerebral artery occlusion. Adult-male Sprague-Dawley rats (n = 60) were divided equally into group 1 (sham-control), group 2 (AIS), group 3 [AIS-ADMSC (1.2×106 cells)], group 4 [AIS-exosome (100μg)], and group 5 (AIS-exosome-ADMSC). All therapies were provided intravenously at 3h after AIS procedure. BIZ determined by histopathology (by day-60) and brain MRI (by day-28) were highest in group 2, lowest in group 1, higher in groups 3 and 4 than in group 5, but they showed no difference between groups 3 and 4 (all p < 0.0001). By day-28, sensorimotor functional results exhibited an opposite pattern to BIZ among the five groups (p < 0.005). Protein expressions of inflammatory (inducible nitric oxide synthase/tumor necrosis factor-α/nuclear factor-κB/interleukin-1β/matrix metalloproteinase-9/plasminogen activator inhibitor-1/RANTES), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/ Poly-ADP-ribose polymerase), and fibrotic (Smad3/transforming growth factor-β) biomarkers, and cellular expressions of brain-damaged (γ-H2AX+/ XRCC1-CD90+/p53BP1-CD90+), inflammatory (CD11+/CD68+/glial fibrillary acid protein+) and brain-edema (aquaporin-4+) markers showed a similar pattern of BIZ among the groups (all n < 0.0001). In conclusion, xenogenic ADMSC/ADMSC-derived exosome therapy was safe and offered the additional benefit of reducing BIZ and improving neurological function in rat AIS.