骨髓间充质干细胞衍生外泌体对脊髓损伤动物治疗作用的系统综述

doi:10.3969/j.issn.1006-9771.2022.05.014

Abstract

Abstract:

Objective To systematically review the efficacy and safety of exosomes derived from bone marrow mesenchymal stem cells (BMSC) on animal models of spinal cord injury. Methods Animal studies about BMSC-derived exosomes for spinal cord injury were retrieved from databases of PubMed, Cochrane Library, Web of Science, CNKI and Wangfang Data, from establishment to October, 2021. Two researchers independently screened and extracted the data, and evaluated the risk of bias. The studies were qualitatively analyzed. Results A total of 21 studies were included, involving 1 342 animals. Male or female Sprague-Dawley rats were selected for 18 studies, and the body mass of the rats was (200±50) g in 19 studies. The injury nodes focused on T_9-11 spinal cord, with various methods. The types, medication time, frequency, concentration and dose of the exosomes were heterogeneous. Conclusions The BMSC-derived exosomes can improve the motor function after spinal cord injury, reduce the damage of spinal cord, resist apoptosis and inflammation, reduce the permeability of blood-spinal cord barrier, and promote the growth of axons and blood vessels. More high-quality studies are needed for further verification.

Key words: spinal cord injury, exosomes, bone marrow mesenchymal stem cells, animal experiment, systematic review

CLC Number:

R651.2

WEI Juanfang,WANG Linjie,CUI Yanru,CEN Qiuyu,ZHANG Anren. Effects of bone marrow mesenchymal stem cells derived exosomes on spinal cord injured animals: a systematic review[J]. 《Chinese Journal of Rehabilitation Theory and Practice》, 2022, 28(5): 585-592.

Figures/Tables 6

纳入研究	动物种属	体质量/ 年龄	n	节段	造模方式	干预措施		结局指标
纳入研究	动物种属	体质量/ 年龄	n	节段	造模方式	T	C	结局指标
Chang等^[10](2021)	雄SD大鼠	220~260 g	72	T₁₀	挫伤：10 g杆12.5 mm高释放	Ⅰ	PBS	①②③④
Chen等^[11](2021)	雄SD大鼠	6~8周	18	T₁₀	钳夹：75 g夹闭30 s	Ⅱ	PBS	①②④⑤⑥
Gu等^[14](2020)	雄SD大鼠	220~260 g	30	T₁₀	挫伤：10 g杆12.5 mm高释放	Ⅱ	PBS	①③
Huang等^[21](2017)	雄SD大鼠	180~220 g	30	T₁₀	挫伤：8 g棒40 mm高释放	Ⅱ	PBS	①③④⑦
Huang等^[19](2021)	雌SD大鼠	200~250 g 10周	100	T₁₀	挫伤：30 g重物50 mm高释放	Ⅱ	PBS	①③④⑤⑧⑨
Jia等^[28](2021)a	雄SD大鼠	230~250 g	40	T₁₀	挫伤：2 N	Ⅱ	生理盐水	①②③
Jia等^[29](2021)b	雄SD大鼠	230~250 g	50	T₁₀	挫伤：2 N	Ⅱ	生理盐水	①②③
Li等^[30](2019)	雄Wistar大鼠	150~200 g	150	T_9-11	挫伤：10 g杆5 cm高释放	Ⅱ	PBS	①②③
Liu等^[31](2022)	雄SD大鼠	250~300 g/ 6~8周	30	T_9-11	挫伤：10 g杆6.5 cm高释放	Ⅱ	PBS	①②④
Liu等^[13](2020)	雄C57BL/6小鼠	6~8周	56	T₁₀	挫伤：5 g杆6.5 cm高释放	Ⅱ	PBS	①②④⑤
Liu等^[32](2019)	雌SD大鼠	170~220 g	20	T₁₀	挫伤：直径2.5 mm打击器12.5 mm高释放	Ⅱ	PBS	①②④
Lu等^[22](2019)	雄SD大鼠	200~250 g	100	T₁₀	挫伤	Ⅱ	PBS	①②③⑩
Luo等^[15](2021)	雌SD大鼠	170~220 g	40	T₁₀	挫伤：10 g杆12.5 mm高释放	Ⅱ	PBS	①②③
Yu等^[33](2019)	雌SD大鼠	230~250 g	80	T₁₀	挫伤：2 N	Ⅱ	PBS	①②
Zhang等^[34](2021)	雄SD大鼠	200~230 g	48	T₉	挫伤：10 g杆12.5 mm高释放	Ⅱ	PBS	①②④
Zhao等^[35](2019)	雄Wistar大鼠	200~250 g	73	T₁₀	横断:虹膜刀水平切断右侧半圆形脊髓	Ⅱ	PBS	①②④?
Zhou等^[5](2022)	雄SD大鼠	200~250 g	160	T₁₀	挫伤：2 N	Ⅱ	PBS	①②③④⑩
董万亮^[36](2020)	雄SD大鼠	约200 g	75	T₁₀	挫伤：20 g棒4.5 cm高释放	Ⅱ	磷酸盐溶液	①?
裴双等^[37](2017)	雄SD大鼠	180~200 g	30	T₁₀	挫伤：2 N	Ⅱ	磷酸盐溶液	①②?
张锐毅^[17](2019)	雄SD大鼠	200~250 g	60	T₁₀	挫伤：2 N	Ⅱ	PBS	①
周燕等^[38](2019)	雄SD大鼠	220~250 g	80	T₁₀	挫伤：20 kPa	Ⅱ	PBS	①③④

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生物效应	作用机制
促进轴突生长	减少硫酸软骨素蛋白聚糖产生,增加生长相关蛋白和神经丝表达,缓解神经传导障碍^[8-9]
促进血管生成	上调参与人脐静脉内皮细胞血管生成的关键基因表达,促进血管内皮生长因子、血管生成素等的表达^[8]
抗炎	促进巨噬细胞M2表型极化,降低炎症因子表达^[10];抑制A1星形胶质细胞活化^[11];抑制脂多糖诱导的NF-κB通路激活^[12];促进小胶质细胞M2表型极化^[13]
抗凋亡	下调caspase-3/9等表达,增加Bcl-2表达,增强Wnt/β-catenin表达^[8,12];促进早期自噬^[14];减少谷氨酸表达^[15]
降低BSCB通透性	通过NF-κB p65通路抑制周细胞迁移^[16];减少claudin-5、ZO-1等的丢失^[17];抑制周细胞焦亡^[5]

结局指标	评定方法
运动功能	①Basso-Beattie-Bresnahan (BBB)评分。②水平爬梯测试^[18]。③运动诱发电位。④尿斑面积定量。⑤热敏度：爪子缩回热潜伏期^[19]。⑥斜板实验^[20]。⑦步态分析^[17]
组织病理学	①HE染色。②免疫荧光Hoechst染色^[11]。③尼氏染色。④透射电子显微镜^[20];Fluoro-Jade B染色^[5]
凋亡	①TUNEL染色^[10]。②凋亡相关标志物^[8]
炎症	①炎性因子和抗炎因子表达^[10]。②炎症相关标志物表达^[11]。③巨噬细胞、小胶质细胞、星形胶质细胞表型极化。④NF-κB信号通路
轴突生长	①免疫荧光染色。②相关基因和蛋白水平^[11]
血管生长	①血管生成相关因子表达^[18]。②内皮细胞免疫荧光染色^[21]
BSCB通透性	①伊文思蓝评估^[22]。②FITC-葡聚糖分析^[23]。③紧密连接蛋白^[17]

结局指标	n	方法学局限性	相关性	结果一致性	数据充分性	总体评价
运动功能	21	21项研究均存在轻微实施偏倚,9项存在轻微评估偏倚,17项存在轻微报告偏倚,1项存在中度报告偏倚	纳入标准与研究问题基本一致	均报告运动功能得到改善	均进行定量分析,资料充分	高
组织病理学	19	19项研究均存在轻微实施偏倚,8项存在轻微评估偏倚,16项存在轻微报告偏倚	纳入标准与研究问题基本一致	均报告脊髓组织病理得到改善	均进行定量或定性分析,资料充分	高
凋亡	11	11项研究均存在轻微实施偏倚,3项存在轻微评估偏倚,10项存在轻微报告偏倚	纳入标准与研究问题基本一致	均报告细胞凋亡得到改善	均进行定量或定性分析,资料相对充分	中
炎症	11	11项研究均存在轻微实施偏倚,5项存在轻微评估偏倚,10项存在轻微报告偏倚	纳入标准与研究问题基本一致	均报告炎症得到改善	均进行定量或定性分析,资料相对充分	中
BSCB通透性	3	3项研究均存在轻微实施偏倚,1项存在轻微评估偏倚,2项存在轻微报告偏倚	纳入标准与研究问题一致	均报告BSCB渗透性得到改善	定性分析,资料不充分	低
轴突生长	1	存在轻微的实施、评估和报告偏倚	纳入标准与研究问题一致	报告轴突生长得到改善	定性分析,资料不充分	低
血管生长	1	存在轻微的实施和报告偏倚	纳入标准与研究问题一致	报告血管生长得到改善	定性分析,资料不充分	低

Effects of bone marrow mesenchymal stem cells derived exosomes on spinal cord injured animals: a systematic review

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