间充质干细胞来源外泌体在骨关节炎治疗中的研究进展

doi:10.3877/cma.j.issn.1674-134X.2022.02.009

骨关节炎(OA)是关节软骨慢性退行性疾病。许多研究表明间充质干细胞(MSCs)可以促进OA的软骨组织修复、改善关节环境等作用。一些MSCs和软骨细胞的共培养实验表明，MSCs可能是通过分泌一些细胞因子发挥作用的，而细胞因子是外泌体(EXs)的重要成分。体外实验证实，间充质干细胞来源的外泌体(MSCs-EXs)与MSCs都具有促进软骨细胞增殖、维持软骨细胞表型、抑制软骨细胞凋亡、促进软骨细胞外基质合成、促进软骨细胞迁移的作用。体内实验也表明，MSCs-EXs在OA中，具有修复软骨、促进软骨基质合成、抑制炎细胞浸润的作用。单纯MSCs-EXs治疗和MSCs治疗相比，具有安全、低成本的优点。这为OA的治疗提供了新的策略。但MSCs-EXs治疗OA的机制尚不明确，本文就MSCs-EXs在OA治疗中的研究进展作一综述。

关键词: 间充质干细胞, 外泌体, 骨关节炎, 软骨细胞

Osteoarthritis (OA) is a chronic degenerative disease of articular cartilage. Many studies have shown that mesenchymal stem cells can promote the repair of cartilage tissue of OA and improve the joint environment. Some co-cultivation experiments of mesenchymal stem cells and chondrocytes indicate that mesenchymal stem cells may act by secreting some cytokines, and exosomes are an important component of these factors.In vitro experiments confirmed that both exosomes and mesenchymal stem cells derived from mesenchymal stem cells can promote chondrocyte proliferation, maintain chondrocyte phenotype, inhibit chondrocyte apoptosis, promote cartilage extracellular matrix synthesis, and promote chondrocyte migration. In vivo experiments have also shown that exosomes derived from mesenchymal stem cells in OA can repair cartilage, promote cartilage matrix synthesis, and inhibit inflammatory cell infiltration. Compared with mesenchymal stem cell therapy, exosomal therapy alone has the advantages of safety and low cost. This provides a new strategy for the treatment of OA. However, the mechanism of MSCs-EXs in the treatment of osteoarthritis is not clear. This article reviewed the research progress of MSCs-EXs in the treatment of OA.

Key words: Mesenchymal stem cells, Exosomes, Osteoarthritis, Chondrocytes

图1 外泌体的生物发生过程注：细胞膜内陷形成早期内体，根据ESCRT(转运必需内体分选复合物)依赖与非ESCRT依赖两种途径选择性包裹多种蛋白质、核酸等而形成多囊体，发育成晚期内体，与细胞膜融合释放外泌体

图2 MSCs-EXs在OA中的作用注：MSC-EXs-间充质干细胞来源外泌体；proliferation-增殖；migration-迁移；differentiation-分化；Collagen II-II型胶原(Col II)；aggrecan-聚集蛋白聚糖(ACAN)；MMP-基质金属蛋白酶；ADAMTS-解整合素-金属蛋白酶；inflammation-炎症；apoptosis-凋亡；关节腔注射MSCs-EXs可促进软骨细胞增殖、迁移、分化，增加Col II、ACAN的表达，以及降低MMP、ADAMTS表达，抑制关节炎症、软骨细胞凋亡

表1 MSCs-EXs-miRNA在OA中的作用及机制

作者	来源细胞	miRNA	靶基因	作用
Chen^[27]^, 2020	BM-MSCs	miR-136-5p	ELF3	促进软骨细胞迁移能力，增加Col Ⅱ、ACAN、SOX9的表达，减少MMP13表达
He^[28]^, 2020	BM-MSCs	miR-210	NF-κB	抗炎，促进软骨细胞增殖，抑制软骨细胞凋亡
Sun^[29]^, 2018	BM-MSCs	miR-320c	/	促进BM-MSCs成软骨分化，促进软骨细胞增殖、迁移及SOX9表达。减低MMP13表达
Dong^[30]^, 2021	BM-MSCs	miR-127-3p	CDH11	抗软骨细胞凋亡，促进Col II表达，减少MMP13表达
Jin^[31]^, 2020	BM-MSCs	miR-9-5p	Syndecan-1	减少软骨缺损，降低IL-1、IL-6、TNF-α、NO、COX2、CRP表达
Wu^[32]^, 2019	髌下脂肪垫的间充质干细胞	miR-100-5p	mTOR	促进软骨细胞Col Ⅱ表达，抑制MMP13、ADAMTS5的表达

表1 MSCs-EXs-miRNA在OA中的作用及机制

作者	来源细胞	miRNA	靶基因	作用
Chen^[27]^, 2020	BM-MSCs	miR-136-5p	ELF3	促进软骨细胞迁移能力，增加Col Ⅱ、ACAN、SOX9的表达，减少MMP13表达
He^[28]^, 2020	BM-MSCs	miR-210	NF-κB	抗炎，促进软骨细胞增殖，抑制软骨细胞凋亡
Sun^[29]^, 2018	BM-MSCs	miR-320c	/	促进BM-MSCs成软骨分化，促进软骨细胞增殖、迁移及SOX9表达。减低MMP13表达
Dong^[30]^, 2021	BM-MSCs	miR-127-3p	CDH11	抗软骨细胞凋亡，促进Col II表达，减少MMP13表达
Jin^[31]^, 2020	BM-MSCs	miR-9-5p	Syndecan-1	减少软骨缺损，降低IL-1、IL-6、TNF-α、NO、COX2、CRP表达
Wu^[32]^, 2019	髌下脂肪垫的间充质干细胞	miR-100-5p	mTOR	促进软骨细胞Col Ⅱ表达，抑制MMP13、ADAMTS5的表达

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