Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.
Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.
复制标题
人间充质基质细胞延迟治疗 2 型糖尿病大鼠中风的神经恢复反应
DOI：
10.1161/strokeaha.116.014686
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发表时间：
2016-11
期刊：
影响因子：
8.3
通讯作者：
Chen J
中科院分区：
文献类型：
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作者：
Yan T;Venkat P;Chopp M;Zacharek A;Ning R;Roberts C;Zhang Y;Lu M;Chen J
糖尿病和中风的共病导致功能结果较差、长期恢复不良和广泛的血管损伤。我们研究了人骨髓源性间充质基质细胞 (hMSC) 对二型糖尿病 (T2DM) 大鼠中风治疗的神经恢复作用和机制。成年雄性Wistar大鼠用T2DM诱导，进行2小时的大脑中动脉闭塞(MCAo)并通过尾静脉注射用以下物质治疗： 1) PBS (n=8)； 2) MCAo后3天的hMSC(n=10, 5×106)。在 T2DM 大鼠中，与 T2DM-MCAo PBS 治疗的大鼠相比，在 MCAo 后 3 天施用 hMSC 显着改善神经功能，而不影响血糖、梗塞体积和脑出血发生率。 T2DM 中风的延迟 hMSC 治疗可显着改善血脑屏障完整性，增加血管和动脉密度以及脑血管灌注，并促进神经母细胞迁移和白质重塑，分别通过增加双皮质素、轴突、髓磷脂和神经丝密度来表明。与 PBS 治疗的 T2DM-MCAo 大鼠相比，延迟 hMSC 治疗显着增加缺血脑中血小板衍生生长因子 (PDGF) 的表达，减少促炎性 M1 巨噬细胞并增加抗炎性 M2 巨噬细胞。体外数据显示，hMSC 增加心室下区外植体细胞迁移和初级皮质神经元轴突生长，而抑制 PDGF 则减少 hMSC 诱导的 SVZ 细胞迁移和轴突生长。在 T2DM 中风大鼠中，延迟 hMSC 治疗可显着改善神经功能结果，并增加神经恢复效果和 M2 巨噬细胞极化。增加大脑 PDGF 表达可能有助于 hMSC 诱导的神经恢复。
Co-morbidity of diabetes mellitus and stroke results in worse functional outcome, poor long term recovery and extensive vascular damage. We investigated the neurorestorative effects and mechanisms of stroke treatment with human bone marrow derived mesenchymal stromal cells (hMSCs) in type two diabetes mellitus (T2DM) rats. Adult male Wistar rats were induced with T2DM, subjected to 2 hours of middle cerebral artery occlusion (MCAo) and treated via tail-vein injection with: 1) PBS (n=8); 2) hMSCs (n=10, 5×106) at 3 days after MCAo. In T2DM rats, hMSCs administered at 3 days after MCAo significantly improves neurological function without affecting blood glucose, infarct volume and incidence of brain hemorrhage in comparison to T2DM-MCAo PBS treated rats. Delayed hMSC treatment of T2DM stroke significantly improves blood brain barrier integrity, increases vascular and arterial density and cerebral vascular perfusion, and promotes neuroblast cell migration and white matter remodeling as indicated by increased doublecortin, axon, myelin and neurofilament density, respectively. Delayed hMSC treatment significantly increases platelet-derived growth factor (PDGF) expression in the ischemic brain, decreases pro-inflammatory M1 macrophage and increases anti-inflammatory M2 macrophage compared to PBS treated T2DM-MCAo rats. In vitro data show that hMSCs increase sub-ventricular zone explant cell migration and primary cortical neuron neurite outgrowth while inhibition of PDGF decreases hMSCs induced SVZ cell migration and axonal outgrowth. In T2DM stroke rats, delayed hMSC treatment significantly improves neurological functional outcome, and increases neurorestorative effects and M2 macrophage polarization. Increasing brain PDGF expression may contribute to hMSC induced neurorestoration.