Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery
Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery
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DOI：
10.1073/pnas.1121146109
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发表时间：
2012-05-08
影响因子：
11.1
通讯作者：
Lo, Eng H.
中科院分区：
文献类型：
--
作者：
Hayakawa, Kazuhide;Pham, Loc-Duyen D.;Lo, Eng H.
越来越多的人怀疑大脑和血液中的全身反应之间的相互作用在中风中起着关键作用。然而，这种沟通是如何发生的，仍有待充分理解。在这里，我们发现反应性星形胶质细胞可以释放一种损伤相关的分子模式分子，称为高迁移率族蛋白1（HMGB1），促进内皮祖细胞（EPC）介导的神经血管重塑中风恢复期间。反应性星形胶质细胞的条件培养基在体外增加EPC增殖。siRNA抑制星形胶质细胞中的HMGB1或阻断EPCs中晚期糖基化终产物的HMGB1受体可防止这种作用。在小鼠局灶性脑缺血模型中，梗死周围皮质中的反应性星形胶质细胞在卒中后14 d上调HMGB1，沿着内源性EPCs的积累。在体内siRNA抑制HMGB1阻断这种EPC反应，减少周围血管生成，并消除神经功能缺损。总之，这些分子和体内研究结果支持了以前未描述的反应性星形胶质细胞和EPCs之间的串扰机制，其中HMGB1促进中风和脑损伤后的神经血管重塑和功能恢复。
Crosstalk between the brain and systemic responses in blood is increasingly suspected of playing critical roles in stroke. However, how this communication takes place remains to be fully understood. Here, we show that reactive astrocytes can release a damage-associated molecular-pattern molecule called high-mobilitygroup-box-1 (HMGB1) that promotes endothelial progenitor cell (EPC)-mediated neurovascular remodeling during stroke recovery. Conditioned media from reactive astrocytes increase EPC proliferation in vitro. siRNA suppression of HMGB1 in astrocytes or blockade of the HMGB1 receptor for advanced glycation end-products in EPCs prevents this effect. In a mouse model of focal cerebral ischemia, reactive astrocytes in the peri-infarct cortex upregulate HMGB1 at 14 d poststroke, along with an accumulation of endogenous EPCs. In vivo siRNA suppression of HMGB1 blocks this EPC response, reduces peri-infact angiogenesis, and worsens neurological deficits. Taken together, these molecular and in vivo findings support a previously undescribed mechanism of crosstalk between reactive astrocytes and EPCs wherein HMGB1 promotes neurovascular remodeling and functional recovery after stroke and brain injury.