BACKGROUND Over the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury. METHODS A systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles. DISCUSSION This systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.

中文翻译：

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疾病动物模型中间充质基质细胞来源的细胞外囊泡的方法和功效：临床前系统评价方案。

背景技术在过去的十年中，人们越来越多地研究间充质基质细胞在几种不同疾病中的治疗潜力。然而，细胞疗法可能受到潜在严重不良事件的限制，包括细胞栓子形成和肿瘤发生。重要的是，间充质基质细胞的保护作用很大程度上是由旁分泌机制介导的，包括细胞外囊泡的释放。本系统综述旨在综合目前关于间充质基质细胞衍生的细胞外囊泡作为疾病、炎症或损伤临床前模型的治疗选择的知识。方法 对 MEDLINE、Embase 和 BIOSIS 数据库进行系统文献检索。将包括使用源自间充质基质细胞的任何组织来源的细胞外囊泡的介入性临床前体内研究。研究将由两名独立评审员按摘要和全文进行筛选。符合条件的研究将进行数据提取，并根据疾病细分为各个领域。将收集用于细胞外囊泡表征和分离的方法，以及有关介入特征的信息，例如间充质基质细胞的组织来源、剂量方案和囊泡修饰。将收集报告的结果，以确定所研究的哪些疾病可能受到间充质基质细胞衍生的细胞外囊泡治疗的影响最大。讨论 本系统综述将总结研究间充质基质细胞衍生的小和大细胞外囊泡治疗功效的临床前研究。细胞外囊泡代表了利用间充质基质细胞的优势的可能性，并具有降低制造成本和提高安全性的额外优势。因此，人们对开发这种无细胞疗法的兴趣呈指数级增长，迄今为止已发表了数百项临床前研究。然而，不同组之间的大量异质性与细胞外囊泡分离、表征和研究设计的方法有关。本综述将捕捉这种异质性，并确定评估间充质基质细胞衍生的细胞外囊泡治疗的最常用和最佳方法。对每个疾病领域的结果进行荟萃分析将有助于阐明哪些研究领域有望开发细胞外囊泡作为一种新型无细胞疗法。总结关于细胞外囊泡作为干预措施的可靠信息，可以为设计临床前研究提供指导，并有望实现未来的临床转化。