Effect of HMGB1 on the Paracrine Action of EPC Promotes Post-Ischemic Neovascularization in Mice
Effect of HMGB1 on the Paracrine Action of EPC Promotes Post-Ischemic Neovascularization in Mice
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HMGB1对EPC旁分泌作用的影响促进小鼠缺血后新生血管形成
DOI：
10.1002/stem.1754
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发表时间：
2014-10-01
期刊：
影响因子：
5.2
通讯作者：
Yang, Guo-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Chao;Lin, Xiaojie;Yang, Guo-Yuan
内皮祖细胞（EPCs）移植可改善实验性卒中的预后，但其机制尚不清楚。研究发现，星形胶质细胞高迁移率族蛋白1（HMGB 1）在脑卒中恢复期促进内源性EPC介导的神经血管重构。目前尚不清楚HMGB 1是否参与外源性EPC介导的卒中恢复。在这项研究中，我们的目的是探讨是否小胶质细胞HMGB 1有助于人外周血来源（hPB）-EPCs介导的神经血管重塑通过调节外源性hPB-EPCs的旁分泌功能。hPB-EPCs与脂多糖共培养刺激BV 2细胞上调hPB-EPCs中IL-8的表达，这被HMGB 1抑制剂甘草酸处理BV 2细胞所阻断。与BV 2细胞共培养的hPB-EPCs的条件培养基（CM）促进了人脐静脉细胞的活力和管形成。抑制HMGB 1或IL-8可阻断hPB-EPCs的CM效应。体内研究表明，hPB-EPCs移植改善了短暂性大脑中动脉闭塞（tMCAO）小鼠的神经行为结局，减少了脑萎缩体积，并增强了新生血管的形成。腹腔注射HMGB 1抑制剂HMGB 1阻断了hPB-EPC移植的有益作用。在tMCAO后第14天，我们没有观察到绿色荧光蛋白标记的hPB-EPCs与梗死周围区域的微血管的整合。综上所述，脑缺血后HMGB 1表达上调可通过调节hPB-EPCs的旁分泌功能促进外源性hPB-EPCs介导的脑卒中恢复。
Transplantation of endothelial progenitor cells (EPCs) leads to better outcomes in experimental stroke, but the mechanism remains unclear. It was reported that astrocytic-high mobility group box1 (HMGB1) promoted endogenous EPC-mediated neurovascular remodeling during stroke recovery. It is unclear whether HMGB1 involves in exogenous EPC-mediated stroke recovery. In this study, we aim to explore whether microglial HMGB1 contributes to human peripheral blood-derived (hPB)-EPCs-mediated neurovascular remodeling by modulating the paracrine function of exogenous hPB-EPCs. Coculturing hPB-EPCs with lipopolysaccharides stimulated BV2 cells upregulated Interleukin-8 expression in hPB-EPCs; this was blocked by treating BV2 cells with HMGB1 inhibitor Glycyrrhizin. Conditioned medium (CM) of hPB-EPCs cocultured with BV2 cells promoted the viability and tube formation of human umbilical cord vein cells. Inhibiting either HMGB1 or IL-8 could block the effect of hPB-EPCs CM. In vivo study showed hPB-EPCs transplantation improved neurobehavioral outcomes, reduced brain atrophy volume, and enhanced neovascularization in transient middle cerebral artery occlusion (tMCAO) mice. Intraperitoneally administration of HMGB1 inhibitor glycyrrhizin blocked the beneficial effect of hPB-EPC transplantation. We did not observe the integration of green fluorescent protein-labeled hPB-EPCs with microvessels in peri-infarct areas at day-14 after tMCAO. In summary, the result suggested that HMGB1 upregulation in postischemic brain could promote exogenous hPB-EPC-mediated stroke recovery by modulating paracrine function of hPB-EPCs.