Progress of mesenchymal stem cell-derived extracellular vesicles in treatment of knee osteoarthritis

doi:10.3877/cma.j.issn.1674-134X.2022.04.014

Abstract

Abstract:

Knee osteoarthritis (KOA) is a chronic degenerative joint degeneration commonly seen in the elderly and is associated with articular cartilage degeneration and subchondral bone remodeling. At present, the treatment of KOA is based on step therapy, including non-surgical primary treatment, pharmacological treatment, restorative treatment, and reconstructive treatment. Mesenchymal stem cells (MSCs) are widely used to treat many diseases, including KOA, because of the great proliferative potential. Extracellular vesicles (EVs) are a promising treatment for KOA by promoting the regeneration of articular cartilage. This review provided feasible theoretical supports for the treatment of KOA with EVs by discussing the mechanism of generation and preparation of EVs, the application of EVs in the treatment of KOA, the efficacy and safety of EVs in the treatment of KOA, and the future outlook of EVs in the treatment of KOA.

Key words: Osteoarthritis, Mesenchymal stem cells, Extracellular vesicles, Cartilage, articular

Ming Ma, Gengxin Jia, Xiaolong Liu, Bin Geng, Yayi Xia. Progress of mesenchymal stem cell-derived extracellular vesicles in treatment of knee osteoarthritis[J]. Chinese Journal of Joint Surgery(Electronic Edition), 2022, 16(04): 472-476.

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References 43

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分离方法	优点	缺点
超速离心^[14](ultra centrifugation，UC)	简便易推广	1.耗时
		2.高剪切力导致的EVs的破裂
		3.产量取决于操作者本身
		4.纯度低
免疫亲和分离^[15](immunoaffinity isolation)	为捕获EVs的最佳方法	仅在高比例EVs存在时有效
沉淀析出^[16](precipitation)	易于使用，设备要求不高	沉淀物易混杂其他样品
色谱定量分析^[17](size exclusion chromatography)	纯度高	易受其他蛋白的影响
超滤^[18](ultrafiltration)	可用于生产高度纯化的多囊泡	易受到材料形状和电荷影响
场流分离^[19](field-flow fractionation)	可以分离不同的EVs亚群	1.只能容纳少量样品
场流分离^[19](field-flow fractionation)	可以分离不同的EVs亚群	2．只能分离不同大小的样本，不能将相同流体动力学尺寸的样本分离

分离方法	优点	缺点
超速离心^[14](ultra centrifugation，UC)	简便易推广	1.耗时
		2.高剪切力导致的EVs的破裂
		3.产量取决于操作者本身
		4.纯度低
免疫亲和分离^[15](immunoaffinity isolation)	为捕获EVs的最佳方法	仅在高比例EVs存在时有效
沉淀析出^[16](precipitation)	易于使用，设备要求不高	沉淀物易混杂其他样品
色谱定量分析^[17](size exclusion chromatography)	纯度高	易受其他蛋白的影响
超滤^[18](ultrafiltration)	可用于生产高度纯化的多囊泡	易受到材料形状和电荷影响
场流分离^[19](field-flow fractionation)	可以分离不同的EVs亚群	1.只能容纳少量样品
场流分离^[19](field-flow fractionation)	可以分离不同的EVs亚群	2．只能分离不同大小的样本，不能将相同流体动力学尺寸的样本分离

作用部位	miRNA/LncRNA	作用机制	效果
关节软骨	miR-23a-3p	抑制PTEN的水平并提高AKT的表达	促进软骨再生^[22]
	miR-23b	下调PKA	诱导软骨分化^[23]
	miR-135b	抑制Sp1表达	促进软骨细胞增殖^[24]
	miR-92a-3p	增强WNT5A的表达	抑制软骨降解^[25]
	miR-210	通过NF-κB通路抑制TNFrsf21的表达	抑制软骨细胞凋亡^[26]
	miR-3677-3p/circRNA_0001236	作用于Sox9轴	减轻软骨降解，抑制OA进展并增强软骨修复^[27]
软骨下骨	miR-210-5p	抑制软骨细胞的耗氧率	抑制软骨下骨的分解^[28]
滑膜	－	促进胶原蛋白生成	促进软骨下骨再生^[29]
滑膜	miR-129-5p	靶向HMGB1的3′UTR末端并抑制IL-1β介导的HMGB1上调	减轻OA的炎症反应^[30]
	miR-26a-5p	延缓滑膜成纤维细胞的损伤	减轻OA的炎症反应

作用部位	miRNA/LncRNA	作用机制	效果
关节软骨	miR-23a-3p	抑制PTEN的水平并提高AKT的表达	促进软骨再生^[22]
	miR-23b	下调PKA	诱导软骨分化^[23]
	miR-135b	抑制Sp1表达	促进软骨细胞增殖^[24]
	miR-92a-3p	增强WNT5A的表达	抑制软骨降解^[25]
	miR-210	通过NF-κB通路抑制TNFrsf21的表达	抑制软骨细胞凋亡^[26]
	miR-3677-3p/circRNA_0001236	作用于Sox9轴	减轻软骨降解，抑制OA进展并增强软骨修复^[27]
软骨下骨	miR-210-5p	抑制软骨细胞的耗氧率	抑制软骨下骨的分解^[28]
滑膜	－	促进胶原蛋白生成	促进软骨下骨再生^[29]
滑膜	miR-129-5p	靶向HMGB1的3′UTR末端并抑制IL-1β介导的HMGB1上调	减轻OA的炎症反应^[30]
	miR-26a-5p	延缓滑膜成纤维细胞的损伤	减轻OA的炎症反应

EVs来源	实验设计	动物模型	结果	安全性	有效性	参考文献
人脐带间充质干细胞	体内和体外实验	大鼠膝关节软骨缺损KOA模型	EVs水凝胶可以修复软骨缺损，促进软骨再生	安全，未提及不良反应	有效	胡红星等人^[22]
人胚胎干细胞系	体内和体外实验	小鼠KOA模型	EVs可减轻KOA对软骨的破坏	安全，未提及不良反应	有效	王亚非等人^[34]
小鼠骨髓	体内和体外实验	小鼠KOA模型	EVs可抑制KOA模型小鼠的软骨降解和骨赘形成，对软骨有保护作用	安全，未提及不良反应	有效	Cosenza等人^[35]
人胚胎干细胞系	体内和体外实验	大鼠骨缺损KOA模型	EVs可促进KOA大鼠软骨缺损的修复	安全，无不良反应发生	有效	Zhang等人^[29]
人类关节腔滑膜组织	体内和体外实验	大鼠KOA模型	EVs可延缓KOA进展，防止膝关节不稳对软骨的损伤	安全，无不良事件发生	有效	陶世聪等人^[33]
兔富含血小板的血浆(PRP)	体内和体外实验	兔KOA模型	PRP来源的EVs可降低KOA引起的炎症反应	安全，无明显不良事件	有效	刘绪昌等人^[37]
人髌骨软骨	体内和体外实验	小鼠KOA模型	EVs可显著改善KOA的软骨损伤，可防止OA的发生	安全，未提及不良反应	有效	段奥等人^[36]

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