CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions.
CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions.
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DOI：
10.3390/cells12141824
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发表时间：
2023-07-11
期刊：
影响因子：
6
通讯作者：
Best, Thomas M. M.
中科院分区：
文献类型：
--
作者：
Kouroupis, Dimitrios;Kaplan, Lee D. D.;Huard, Johnny;Best, Thomas M. M.
关键词：
人类炎症性关节疾病的发生和发展与常驻滑膜/髌下脂肪垫(IFP)的激活、促炎和疼痛传递信号密切相关。我们最近报道，关节内注射IFP来源的间充质干细胞(IFP-MSC)获得了强大的免疫调节表型，并通过中性内肽酶CD10(Neprilysin)主动降解P物质(SP)。我们的假设是，IFP-MSC强大的免疫调节治疗作用主要是通过其CD10结合的小细胞外小泡(IFP-MSC SEV)来发挥的，从而减轻滑膜细胞的促炎活性和关节软骨的降解。在此，从CD10High和CD10Low表达的IFP-MSC培养物中分离出IFP-MSC SEV，并用多重方法鉴定其SEV miRNA载量。在功能上，我们考察了CD10High和CD10Low SEV对炎症/纤维化信号、滑膜细胞单一培养以及与IFP-MSC来源的软骨颗粒共培养的影响。最后，在急性滑膜炎/脂肪垫纤维化的动物模型中，对CD10High SEV的体内治疗能力进行了测试。我们的结果表明，CD10High和CD10Low SEV具有不同的miRNA图谱。对SEV中高度存在的miRNAs进行的反应组学分析表明，它们参与了六个基因组的调节，特别是涉及免疫系统的基因。与对照刺激的滑膜细胞相比，暴露于IFP-MSC SEV的刺激滑膜细胞的增殖显著减少，并改变了炎症相关的分子特征。重要的是，CD10High SEV处理刺激的软骨颗粒/滑膜细胞共培养显示了显著的软骨保护作用。在治疗方面，CD10High SEV治疗通过在急性滑膜炎/IFP纤维化动物模型中保留关节软骨结构/成分和PRG4(润滑素)表达的软骨细胞而产生强大的软骨保护作用。我们的研究表明，CD10High SEV具有免疫调节的miRNA属性，对体内关节软骨具有很强的软骨保护/合成代谢作用。这一结果可以作为基于SEV的疗法的基础，用于解决与骨关节炎(OA)等疾病相关的免疫介导的炎性关节变化的有害方面。
The onset and progression of human inflammatory joint diseases are strongly associated with the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived mesenchymal stem/stromal cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic effects are largely exerted via their CD10-bound small extracellular vesicles (IFP-MSC sEVs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC sEVs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their sEV miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low sEVs on stimulated by inflammatory/fibrotic cues synoviocyte monocultures and cocultures with IFP-MSC-derived chondropellets. Finally, CD10High sEVs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low sEVs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in sEVs showed their involvement in the regulation of six gene groups, particularly those involving the immune system. Stimulated synoviocytes exposed to IFP-MSC sEVs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High sEV treatment of stimulated chondropellets/synoviocyte cocultures indicated significant chondroprotective effects. Therapeutically, CD10High sEV treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High sEVs possess immunomodulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for sEV-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).
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DOI：
10.3390/bioengineering8110166
发表时间：
2021-10-29
期刊：
Bioengineering (Basel, Switzerland)
影响因子：
--
作者：
Kouroupis D;Best TM;Kaplan LD;Correa D;Griswold AJ
通讯作者：
Griswold AJ
影响因子：
4.6
作者：
Kouroupis D;Kaplan LD;Best TM
通讯作者：
Best TM
影响因子：
4.4
作者：
Jurkin, Jennifer;Schichl, Yvonne M.;Strobl, Herbert
通讯作者：
Strobl, Herbert
影响因子：
--
作者：
Jones, EA;Kinsey, SE;McGonagle, D
通讯作者：
McGonagle, D
影响因子：
3.9
作者：
De Luca, Paola;Kouroupis, Dimitrios;Colombini, Alessandra
通讯作者：
Colombini, Alessandra