诱导型神经干细胞对颅脑创伤后免疫细胞的影响

doi:10.3877/cma.j.issn.2095-9141.2017.06.008

中华神经创伤外科电子杂志 ›› 2017, Vol. 03 ›› Issue (06) : 355 -359. doi: 10.3877/cma.j.issn.2095-9141.2017.06.008

所属专题：文献；

基础研究

诱导型神经干细胞对颅脑创伤后免疫细胞的影响

高谋¹, 徐如祥¹^,^†(

), 王海峰², 许民辉¹, 董勤¹, 姚慧¹, 张岩¹, 杨阳¹, 党圆圆¹, 张洪钿¹, 杨志军¹

^1. 100700　北京，陆军总医院附属八一脑科医院
^2. 130021　长春，吉林大学第一医院神经创伤外科

收稿日期:2017-10-26 出版日期:2017-12-15
通信作者: 徐如祥
基金资助:
国家自然科学基金(81671189); 全军"十三五"军事医学创新工程项目(16CXZ001)

Effects of induced neural stem cells on immune cells following traumatic brain injury

Mou Gao¹, Ruxiang Xu¹^,^†(), Haifeng Wang², Minhui Xu¹, Qin Dong¹, Hui Yao¹, Yan Zhang¹, Yang Yang¹, Yuanyuan Dang¹, Hongtian Zhang¹, Zhijun Yang¹

^1. Affiliated Bayi Brain Hospital, General Hospital of PLA Army, Beijing 100700, China
^2. Department of Neurotrauma, First Hospital of Jilin University, Changchun 130021, China

Received:2017-10-26 Published:2017-12-15
Corresponding author: Ruxiang Xu
About author:
Corresponding author: Xu Ruxiang, Email: zjxuruxiang@163.com

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引用本文：

高谋, 徐如祥, 王海峰, 许民辉, 董勤, 姚慧, 张岩, 杨阳, 党圆圆, 张洪钿, 杨志军. 诱导型神经干细胞对颅脑创伤后免疫细胞的影响[J/OL]. 中华神经创伤外科电子杂志, 2017, 03(06): 355-359.

Mou Gao, Ruxiang Xu, Haifeng Wang, Minhui Xu, Qin Dong, Hui Yao, Yan Zhang, Yang Yang, Yuanyuan Dang, Hongtian Zhang, Zhijun Yang. Effects of induced neural stem cells on immune cells following traumatic brain injury[J/OL]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2017, 03(06): 355-359.

目的

研究诱导型神经干细胞（iNSCs）移植对颅脑创伤（TBI）后小胶质细胞活化状态和反应性星形胶质细胞增生的影响。

方法

采用自由落体脑打击装置制备C57BL/6小鼠TBI模型，将1×10⁶个iNSCs移植到TBI小鼠脑内，于移植后7 d处死动物，取材进行形态学研究。用双重免疫荧光染色，分别观察iNSCs移植对TBI小鼠脑内ED1和Iba1抗体双阳性的小胶质细胞、GFAP抗体阳性星形胶质细胞以及NeuN抗体阳性神经元的影响。

结果

TBI后小鼠脑内可见大量ED1和Iba1抗体双阳性的小胶质细胞和GFAP抗体阳性的星形胶质细胞，而iNSCs移植物明显减少了ED1和Iba1抗体双阳性的小胶质细胞和GFAP抗体阳性的星形胶质细胞的数量，并且明显减轻了NeuN抗体阳性的神经元的凋亡。

结论

iNSCs移植物在TBI小鼠脑内，可调控小胶质细胞活化状态，抑制反应性星形胶质细胞增生，有利于神经元存活。

关键词: 诱导型神经干细胞, 小胶质细胞, 星形胶质细胞, 颅脑创伤, 移植

Objective

To study the effects of grafted induced neural stem cells (iNSCs) on microglia activation states and reactive astrogliosis following traumatic brain injury (TBI).

Methods

TBI models were established using a standardized weight-drop device. At 12 h after TBI, a total of 1×10⁶ iNSCs were transplanted into the brains of TBI mice. On day 7 after TBI, animals were sacrificed for morphological analysis. Double-labeling experiments were utilized to determine the effects of iNSC grafts on ED1-and Iba1-positive microglia, GFAP-positive astrocytes and NeuN-positive neurons in the brains of TBI mice.

Results

Following TBI, we observed dramatic increases in the numbers of ED1- and Iba1-positive microglia and GFAP-positive astrocytes in the brains of TBI mice. However, grafted iNSCs significantly suppressed the numbers of ED1- and Iba1-positive microglia and GFAP-positive astrocytes in the brains of TBI mice. Additionally, iNSC grafts substantially reduced the levels of apoptotic NeuN-positive neurons in the brains of TBI mice.

Conclusion

INSC grafts can modulate microglia activation states and inhibit reactive astrogliosis to promote neuronal survival post-TBI.

Key words: Induced neural stem cell, Microglia, Astrocyte, Traumatic brain injury, Transplantation

图1 诱导型神经干细胞移植物减少颅脑损伤小鼠脑内ED1和Iba1抗体双阳性的小胶质细胞数量（×400）

表1 颅脑损伤后7 d，各组小鼠脑内特异性抗体标记细胞的百分率（±s，%）

组别	只数	ED1和Iba1抗体双阳性的小胶质细胞	GFAP抗体阳性星形胶质细胞	NeuN抗体阳性神经元
sham组	6	1.40±0.33	11.24±1.63	58.71±4.07
iNSCs移植组	6	21.40±2.04^a	21.95±1.94^a	21.29±1.96^a
PBS处理组	6	29.39±2.89^ab	29.50±2.27^ab	16.45±1.52^ab
F值	?	296.320	131.030	424.000
P值	?	0.000	0.000	0.000

表1 颅脑损伤后7 d，各组小鼠脑内特异性抗体标记细胞的百分率（±s，%）

组别	只数	ED1和Iba1抗体双阳性的小胶质细胞	GFAP抗体阳性星形胶质细胞	NeuN抗体阳性神经元
sham组	6	1.40±0.33	11.24±1.63	58.71±4.07
iNSCs移植组	6	21.40±2.04^a	21.95±1.94^a	21.29±1.96^a
PBS处理组	6	29.39±2.89^ab	29.50±2.27^ab	16.45±1.52^ab
F值	?	296.320	131.030	424.000
P值	?	0.000	0.000	0.000

图2 诱导型神经干细胞移植物减少颅脑损伤小鼠脑内GFAP抗体阳性星形胶质细胞数量（×400）

[1]	Goldman SA. Stem and progenitor cell-based therapy of the central nervous system: hopes, hype, and wishful thinking[J]. Cell Stem Cell, 2016, 18(2): 174-188.
[2]	Yao H,Gao M,Ma J, et al. Transdifferentiation-induced neural stem cells promote recovery of middle cerebral artery stroke rats[J]. PloS One, 2015, 10(9): e0137211.
[3]	Gao M,Yao H,Dong Q, et al. Tumourigenicity and immunogenicity of induced neural stem cell grafts versus induced pluripotent stem cell grafts in syngeneic mouse brain[J]. Sci Rep, 2016, 6: 29955.
[4]	高谋,徐如祥,许民辉,等.诱导神经干细胞与诱导多能干细胞在同源宿主脑内的致瘤性及免疫原性研究[J].中华神经创伤外科电子杂志, 2016, 2(6): 350-354.
[5]	Kim HS,Kim J,Jo Y, et al. Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors[J]. Stem Cell Res, 2014, 12(1): 60-68.
[6]	Kokaia Z,Martino G,Schwartz M, et al. Cross-talk between neural stem cells and immune cells: the key to better brain repair[J]. Nat Neurosci, 2012, 15(8): 1078-1087.
[7]	Gao M,Yao H,Dong Q, et al. Neurotrophy and immunomodulation of induced neural stem cell grafts in a mouse model of closed head injury[J]. Stem Cell Res, 2017, 23: 132-142.
[8]	高谋,徐如祥,杨志军,等.两种干细胞对颅脑创伤炎症反应调控作用的对比研究[J].第三军医大学学报, 2015, 37(17): 1697-1703.
[9]	Cartier N,Lewis CA,Zhang R, et al. The role of microglia in human disease: therapeutic tool or target[J]. ActaNeuropathol, 2014, 128(3): 363-380.
[10]	Amor S,Woodroofe MN. Innate and adaptive immune responses in neurodegeneration and repair[J]. Immunology, 2014, 141(3): 287-291.
[11]	Sofroniew MV. Astrocyte barriers to neurotoxic inflammation[J]. Nat Rev Neurosci, 2015, 16(5): 249-263.
[12]	Corps KN,Roth TL,McGavern DB. Inflammation and neuroprotection in traumatic brain injury[J]. JAMA Neurol, 2015, 72(3): 355-362.
[13]	Kumar A,Barrett JP,Alvarez-Croda DM, et al. NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury[J]. Brain BehavImmun, 2016, 58: 291-309.
[14]	Hernandez-Ontiveros DG,Tajiri N,Acosta S, et al. Microglia activation as a biomarker for traumatic brain injury[J]. Front Neurol, 2013, 4: 30.
[15]	Mouzon BC,Bachmeier C,Ferro A, et al. Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model[J]. Ann Neurol, 2014, 75(2): 241-254.
[16]	Glushakova OY,Johnson D,Hayes RL. Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage[J]. J Neurotrauma, 2014, 31(13): 1180-1193.
[17]	Mayo L,Trauger SA,Blain M, et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation[J]. Nat Med, 2014, 20(10): 1147-1156.
[18]	Rothhammer V,Mascanfroni ID,Bunse L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor[J]. Nat Med, 2016, 22(6): 586-597.
[19]	Xanthos DN,Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity[J]. Nat Rev Neurosci, 2014, 15(1): 43-53.

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