Bernardi Luis Pedro, Hugentobler Schlickmann Thomas, Carello-Collar Giovanna, De Bastiani Marco Antonio, Rigon Zimmer Eduardo, Braganhol Elizandra, Rohden Francieli, Souza Diogo Onofre
Biological Sciences Graduate Program: Biochemistry, Department of Biochemistry, Institute of Health Basic Sciences, Federal University of Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil.
Faculty of Medicine, Institute of Health Basic Sciences, Federal University of Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil.
Mol Neurobiol. 2025 May 22. doi: 10.1007/s12035-025-05025-x.
The modulation of microglial reactivity has emerged as a potential target for developing ischemic stroke therapies. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) possess immunomodulatory properties that may influence microglial responses following ischemia. However, individual studies assessing this influence have provided limited results. Therefore, we conducted a systematic review and meta-analysis to investigate whether MSC-EVs treatment alters microglial responses in animal and cellular models of ischemic stroke. In accordance with the PRISMA 2020 statement, we searched PubMed, Web of Science, and EMBASE until October 2023 for studies assessing cellular and molecular parameters of microglial reactivity following MSC-EVs treatment in models of ischemic stroke. We estimated treatment effects using a random-effects meta-analysis of standardized mean differences and estimated heterogeneity via the I statistic. The risk of bias was assessed using the SYRCLE questionnaire. The search identified 297 studies, 27 of which met the inclusion criteria. In animal models, MSC-EVs reduced the number, surface area, and fluorescence intensity of Iba1 cells, as well as the number of Iba1 cells co-expressing the pro-inflammatory markers CD16, CD32, CD85, and iNOS. Conversely, MSC-EVs increased the number of Iba1 cells co-expressing the anti-inflammatory markers Arg-1 and CD206. In cellular models, we observed decreased concentrations of TNF-α, IL-1β, and IL-6 in the culture medium. Our meta-analysis consolidates the immunomodulatory effects of MSC-EVs on microglial responses to ischemia, underscoring the potential of microglia-specific therapeutics in the development of MSC-EVs-based and regenerative treatments for ischemic stroke.
小胶质细胞反应性的调节已成为开发缺血性中风治疗方法的一个潜在靶点。间充质干细胞衍生的细胞外囊泡（MSC-EVs）具有免疫调节特性，可能会影响缺血后的小胶质细胞反应。然而，评估这种影响的个别研究结果有限。因此，我们进行了一项系统评价和荟萃分析，以研究MSC-EVs治疗是否会改变缺血性中风动物模型和细胞模型中的小胶质细胞反应。根据PRISMA 2020声明，我们检索了PubMed、科学网和EMBASE，直至2023年10月，以查找评估在缺血性中风模型中MSC-EVs治疗后小胶质细胞反应性的细胞和分子参数的研究。我们使用标准化均数差的随机效应荟萃分析估计治疗效果，并通过I统计量估计异质性。使用SYRCLE问卷评估偏倚风险。检索共识别出297项研究，其中27项符合纳入标准。在动物模型中，MSC-EVs减少了Iba1细胞的数量、表面积和荧光强度，以及共表达促炎标志物CD16、CD32、CD85和诱导型一氧化氮合酶的Iba1细胞数量。相反，MSC-EVs增加了共表达抗炎标志物精氨酸酶-1和CD206的Iba1细胞数量。在细胞模型中，我们观察到培养基中肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6的浓度降低。我们的荟萃分析巩固了MSC-EVs对小胶质细胞缺血反应的免疫调节作用，强调了小胶质细胞特异性疗法在开发基于MSC-EVs的缺血性中风再生治疗中的潜力。
