Applications and advances of mesenchymal stem cells-derived exosomes in treating neurodegenerative diseases

doi:10.3877/cma.j.issn.2095-1221.2023.02.005

Abstract

Abstract:

With the advent of the aging era, the number of people suffering from neurodegenerative diseases has dramatically increased. Neurodegenerative diseases severely reduce the quality of life and life cycle of patients, and there is still a lack of effective treatments worldwide. Mesenchymal stem cells-derived exosomes (MSC-exos), rich in functional bioactive substances, have opened up a whole novel direction for treating neurodegenerative diseases as a new pathway for intercellular communication. This novel cell-free therapy has shown great potential in reducing neuroinflammation, inhibiting neural cell death, and inducing neural regeneration in preclinical and clinical studies. In addition, it has various advantages over conventional therapies, such as easy passage through the blood-brain barrier, high safety, and low immunogenicity. This review focuses on the latest research on MSC-exos for the treatment of chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. It presents a discussion and outlook to promote the basic research and clinical application of MSC-exos in neurodegenerative diseases.

Key words: Neurodegenerative diseases, Mesenchymal stem cells, Exosomes

Shuangyin Lei, Jianxin Xi, Yuxuan He, Jingyi Yao, Boya Shi, Jie Ma, Guangfan Chi, Meiying Li. Applications and advances of mesenchymal stem cells-derived exosomes in treating neurodegenerative diseases[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(02): 93-100.

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References 85

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组织来源	治疗细胞/动物	治疗方式	作用机制	治疗效应	参考文献
骨髓	APP/PS1小鼠	静脉注射	激活SphK/S1P信号通路，抑制Aβ沉积，增加NeuN表达	提高小鼠的空间学习和记忆能力	[25]
骨髓	APP/PS1小鼠及其原代培养神经元	脑室内注射	抑制Aβ诱导的iNOS表达	缓解突触损伤，改善了小鼠认知行为	[26]
骨髓	AD大鼠（通过在SD大鼠侧脑室注射Aβ建立）及AD体外细胞模型	侧脑室内注射	将miR-29c-3p递送至神经元，以抑制β-分泌酶表达并激活Wnt/β-catenin通路	减少Aβ沉积面积和斑块，增加体外AD海马神经元活力	[27]
骨髓	3xTg-AD小鼠	鼻内给药	促使小胶质细胞极化为抗炎表型并增加了树突棘密度	抑制小胶质细胞激活，调控神经炎症，发挥神经保护作用	[28]
骨髓	AD小鼠（通过在C57BL/6小鼠脑室注射STZ建立）	侧脑室注射	抑制海马区小胶质细胞和星形胶质细胞过度活化，下调促炎细胞因子表达，上调突触功能相关蛋白表达	减轻中枢神经系统炎症，改善注射STZ的小鼠的AD样行为	[29]
骨髓	海马神经元	—	抑制Aβ诱导的氧化应激和突触损伤	保护海马神经元免受Aβ的毒害	[30]
脐带	J20-AD小鼠及具有家族性AD突变的神经细胞培养模型	静脉注射	下调HDAC4表达，恢复突触可塑性相关基因表达	改善AD小鼠脑葡萄糖代谢和认知功能	[31]
脐带	APP/PS1小鼠	脑室内注射	减少Aβ水平、炎症反应和氧化应激，抑制小胶质细胞活化	改善小鼠空间学习能力和认知缺陷	[32]
脂肪	转基因小鼠衍生的AD体外模型	—	降低Aβ水平，增加促凋亡蛋白表达	改善Aβ诱导的神经元凋亡	[33]

组织来源	治疗细胞/动物	治疗方式	作用机制	治疗效应	参考文献
骨髓	APP/PS1小鼠	静脉注射	激活SphK/S1P信号通路，抑制Aβ沉积，增加NeuN表达	提高小鼠的空间学习和记忆能力	[25]
骨髓	APP/PS1小鼠及其原代培养神经元	脑室内注射	抑制Aβ诱导的iNOS表达	缓解突触损伤，改善了小鼠认知行为	[26]
骨髓	AD大鼠（通过在SD大鼠侧脑室注射Aβ建立）及AD体外细胞模型	侧脑室内注射	将miR-29c-3p递送至神经元，以抑制β-分泌酶表达并激活Wnt/β-catenin通路	减少Aβ沉积面积和斑块，增加体外AD海马神经元活力	[27]
骨髓	3xTg-AD小鼠	鼻内给药	促使小胶质细胞极化为抗炎表型并增加了树突棘密度	抑制小胶质细胞激活，调控神经炎症，发挥神经保护作用	[28]
骨髓	AD小鼠（通过在C57BL/6小鼠脑室注射STZ建立）	侧脑室注射	抑制海马区小胶质细胞和星形胶质细胞过度活化，下调促炎细胞因子表达，上调突触功能相关蛋白表达	减轻中枢神经系统炎症，改善注射STZ的小鼠的AD样行为	[29]
骨髓	海马神经元	—	抑制Aβ诱导的氧化应激和突触损伤	保护海马神经元免受Aβ的毒害	[30]
脐带	J20-AD小鼠及具有家族性AD突变的神经细胞培养模型	静脉注射	下调HDAC4表达，恢复突触可塑性相关基因表达	改善AD小鼠脑葡萄糖代谢和认知功能	[31]
脐带	APP/PS1小鼠	脑室内注射	减少Aβ水平、炎症反应和氧化应激，抑制小胶质细胞活化	改善小鼠空间学习能力和认知缺陷	[32]
脂肪	转基因小鼠衍生的AD体外模型	—	降低Aβ水平，增加促凋亡蛋白表达	改善Aβ诱导的神经元凋亡	[33]

组织来源	治疗细胞/动物	治疗方式	作用机制	治疗效应	参考文献
骨髓	PD大鼠（通过在Wistar-Han雄性大鼠脑室注射6-OHDA建立）	黑质内纹状体给药	VEGF、BDNF、IL-6、GDNF和PEDF表达增多	部分恢复PD大鼠的运动表型和神经元结构	[46]
骨髓	6-OHDA刺激的PD体外细胞模型	—	稳定了生理α-syn单体，并减少了聚集的不溶性p-S129 α-syn，上调了Bax/Bcl-2的比例	减少鱼藤酮诱导的细胞死亡，促进神经再生	[47]
骨髓	α-syn诱导的线虫	—	减少α-syn聚集物的数量	减轻线虫多巴胺能神经变性，从而神经保护作用	[48]
骨髓	PD大鼠（通过在Wistar-Han雄性大鼠大鼠脑室注射6-OHDA建立）	静脉注射	UPS依赖性蛋白质平衡的恢复	减少多巴胺能神经元的死亡，恢复PD大鼠运动功能	[49]
骨髓	PD大鼠（通过在SD大鼠皮下注射鱼藤酮建立）	静脉注射	血清TGF-β1和MCP-1水平大幅下降，血清BDNF和脑多巴胺水平以及脑TH和巢蛋白基因表达显着升高	促进大鼠自体神经元再生和移植细胞分化为神经细胞，恢复纹状体组织结构完整	[50]
脐带	PD小鼠（通过在C57BL/6小鼠腹膜内注射MPTP建立）	静脉注射	抑制NLRP3炎症小体在中枢和外周器官中的表达	抑制黑质中小胶质细胞活化，减轻了神经炎症，缓解了小鼠的PD样行为	[51]
脂肪	促氧化剂（H₂O₂）和6-OHDA处理的人神经母细胞瘤SH-SY5Y细胞	—	上调SIRT3水平	减少ROS生成，减弱氧化应激，起到神经保护作用	[52]

组织来源	治疗细胞/动物	治疗方式	作用机制	治疗效应	参考文献
骨髓	PD大鼠（通过在Wistar-Han雄性大鼠脑室注射6-OHDA建立）	黑质内纹状体给药	VEGF、BDNF、IL-6、GDNF和PEDF表达增多	部分恢复PD大鼠的运动表型和神经元结构	[46]
骨髓	6-OHDA刺激的PD体外细胞模型	—	稳定了生理α-syn单体，并减少了聚集的不溶性p-S129 α-syn，上调了Bax/Bcl-2的比例	减少鱼藤酮诱导的细胞死亡，促进神经再生	[47]
骨髓	α-syn诱导的线虫	—	减少α-syn聚集物的数量	减轻线虫多巴胺能神经变性，从而神经保护作用	[48]
骨髓	PD大鼠（通过在Wistar-Han雄性大鼠大鼠脑室注射6-OHDA建立）	静脉注射	UPS依赖性蛋白质平衡的恢复	减少多巴胺能神经元的死亡，恢复PD大鼠运动功能	[49]
骨髓	PD大鼠（通过在SD大鼠皮下注射鱼藤酮建立）	静脉注射	血清TGF-β1和MCP-1水平大幅下降，血清BDNF和脑多巴胺水平以及脑TH和巢蛋白基因表达显着升高	促进大鼠自体神经元再生和移植细胞分化为神经细胞，恢复纹状体组织结构完整	[50]
脐带	PD小鼠（通过在C57BL/6小鼠腹膜内注射MPTP建立）	静脉注射	抑制NLRP3炎症小体在中枢和外周器官中的表达	抑制黑质中小胶质细胞活化，减轻了神经炎症，缓解了小鼠的PD样行为	[51]
脂肪	促氧化剂（H₂O₂）和6-OHDA处理的人神经母细胞瘤SH-SY5Y细胞	—	上调SIRT3水平	减少ROS生成，减弱氧化应激，起到神经保护作用	[52]

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