骨髓间充质干细胞在脑梗死急性期调节大鼠梗死灶周围区小胶质细胞的激活。
Bone marrow-mesenchymal stem cells modulate microglial activation in the peri-infarct area in rats during the acute phase of stroke.
机构信息
Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
Geriatric Department, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
出版信息
Brain Res Bull. 2019 Nov;153:324-333. doi: 10.1016/j.brainresbull.2019.10.001. Epub 2019 Oct 4.
AIM
Bone marrow-mesenchymal stem cells (BM-MSCs) possess immunomodulatory properties in the brain. However, it remains unclear whether intravenously transplanted BM-MSCs have a neuromodulator effect on the activation of microglias after ischemic stroke. This study aimed to investigate the immunomodulatory effect of BM-MSCs on the regulation of brain microglial inactivation during the acute phase of stroke.
METHODS
A rat model of middle cerebral artery occlusion (MCAO) was established. Rat BM-MSCs were transplanted through the tail vein at 12 h after MCAO. CD200 Receptor 1 (CD200R1) antibody was injected into the peri-infarct area of the rat brain at 3 h prior to BM- MSCs transplantation. Protein expression was determined by immunofluorescence staining and Western blot. The volume of the infarct area was determined by TTC (2,3,5-triphenyltetrazolium hydrochloride) staining. Neuron apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.
RESULTS
In vitro study showed that co-culture with BM-MSCs significantly decreased LPS-induced iNOS expression in the microglial cells. Immunofluorescence and Western blot consistently revealed that BM-MSC transplantation significantly reduced the IBA-expressing microglial cells and IBA protein levels in the peri-infarct area. The inhibitory effect of BM-MSC on IBA expression was significantly attenuated by pretreatment of CD200R1 neutralizing antibody in the peri-infarct zone. BM-MSC transplantation significantly reduced the infarct volume, protected neuron apoptosis, and increased neuronal CD200 expression in the peri-infarct area.
CONCLUSION
The transplanted BM-MSCs exerted immunomodulatory effect by inactivating the microglias in the peri-infarct area, at least partially, via the CD200-CD200R1 signaling.
目的
骨髓间充质干细胞（BM-MSCs）在脑内具有免疫调节特性。然而，静脉移植的 BM-MSCs 是否对缺血性中风后小胶质细胞的激活具有神经调节作用尚不清楚。本研究旨在探讨 BM-MSCs 对中风急性期大脑小胶质细胞失活的免疫调节作用。
方法
建立大脑中动脉闭塞（MCAO）大鼠模型。MCAO 后 12 小时通过尾静脉移植大鼠 BM-MSCs。在 BM-MSCs 移植前 3 小时，将 CD200 受体 1（CD200R1）抗体注射到大鼠脑梗死周边区。通过免疫荧光染色和 Western blot 测定蛋白表达。通过 TTC（2,3,5-三苯基四唑氯化物）染色测定梗死面积。通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）染色测定神经元凋亡。
结果
体外研究表明，与 BM-MSCs 共培养可显著降低 LPS 诱导的小胶质细胞中 iNOS 的表达。免疫荧光和 Western blot 一致显示，BM-MSC 移植可显著减少梗死周边区 IBA 表达的小胶质细胞和 IBA 蛋白水平。在梗死周边区预先给予 CD200R1 中和抗体可显著减弱 BM-MSC 对 IBA 表达的抑制作用。BM-MSC 移植可显著减少梗死体积，保护神经元凋亡，并增加梗死周边区神经元 CD200 的表达。
结论
移植的 BM-MSCs 通过 CD200-CD200R1 信号通路至少部分地通过使梗死周边区的小胶质细胞失活来发挥免疫调节作用。
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