内皮祖细胞移植通过缺氧诱导因子-1α减轻糖尿病小鼠缺血后脑血屏障损伤。
Endothelial progenitor cells transplantation attenuated blood-brain barrier damage after ischemia in diabetic mice via HIF-1α.
作者信息
Geng Jieli, Wang Liping, Qu Meijie, Song Yaying, Lin Xiaojie, Chen Yajing, Mamtilahun Muyassar, Chen Shengdi, Zhang Zhijun, Wang Yongting, Yang Guo-Yuan
机构信息
Department of Neurology, Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
Department of Neurology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
出版信息
Stem Cell Res Ther. 2017 Jul 11;8(1):163. doi: 10.1186/s13287-017-0605-3.
BACKGROUND
Blood-brain barrier impairment is a major indicator of endothelial dysfunction in diabetes. Studies showed that endothelial progenitor cell (EPC) transplantation promoted angiogenesis and improved function recovery after hind limb ischemia in diabetic mice. The effect of EPC transplantation on blood-brain barrier integrity after cerebral ischemia in diabetic animals is unknown. The aim of this study is to explore the effect of EPC transplantation on the integrity of the blood-brain barrier after cerebral ischemia in diabetic mice.
METHODS
EPCs were isolated by density gradient centrifugation and characterized by flow cytometry and immunostaining. Diabetes was induced in adult male C57BL/6 mice by a single injection of streptozotocin at 4 weeks before surgery. Diabetic mice underwent 90-minute transient middle cerebral artery occlusion surgery and received 1 × 10 EPCs transplantation immediately after reperfusion. Brain infarct volume, blood-brain barrier permeability, tight junction protein expression, and hypoxia inducible factor-1α (HIF-1α) mRNA level were examined after treatment.
RESULTS
We demonstrated that neurological deficits were attenuated and brain infarct volume was reduced in EPC-transplanted diabetic mice after transient cerebral ischemia compared to the controls (p < 0.05). Blood-brain barrier leakage and tight junction protein degradation were reduced in EPC-transplanted mice (p <0.05). EPCs upregulated HIF-1α expression while HIF-1α inhibitor PX-478 abolished the beneficial effect of EPCs.
CONCLUSIONS
We conclude that EPCs protected blood-brain barrier integrity after focal ischemia in diabetic mice through upregulation of HIF-1α signaling.
背景
血脑屏障损伤是糖尿病血管内皮功能障碍的主要指标。研究表明，内皮祖细胞（EPC）移植可促进血管生成，并改善糖尿病小鼠后肢缺血后的功能恢复。EPC移植对糖尿病动物脑缺血后血脑屏障完整性的影响尚不清楚。本研究的目的是探讨EPC移植对糖尿病小鼠脑缺血后血脑屏障完整性的影响。
方法
通过密度梯度离心法分离EPC，并通过流式细胞术和免疫染色进行鉴定。在手术前4周，通过单次注射链脲佐菌素诱导成年雄性C57BL/6小鼠患糖尿病。糖尿病小鼠接受90分钟的短暂大脑中动脉闭塞手术，并在再灌注后立即接受1×10个EPC移植。治疗后检测脑梗死体积、血脑屏障通透性、紧密连接蛋白表达和缺氧诱导因子-1α（HIF-1α）mRNA水平。
结果
我们证明，与对照组相比，短暂性脑缺血后接受EPC移植的糖尿病小鼠神经功能缺损减轻，脑梗死体积减小（p<0.05）。接受EPC移植的小鼠血脑屏障渗漏和紧密连接蛋白降解减少（p<0.05）。EPC上调HIF-1α表达，而HIF-1α抑制剂PX-478消除了EPC的有益作用。
结论
我们得出结论，EPC通过上调HIF-1α信号通路保护糖尿病小鼠局灶性缺血后的血脑屏障完整性。
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