Abstract：
BACKGROUND: Asthma is a common disease, and among the most predominant causes of the years lived with disability. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising avenue for asthma management. The objective of this study is to perform a systematic review and meta-analysis of pre-clinical studies investigating the therapeutic use of MSC-EVs in murine models of asthma.
METHODS: A systematic search of electronic databases was performed. Meta-analyses were conducted on broncho-alveolar lavage fluid (BALF) cells and cytokines, as well as airway hyper-responsiveness Penh values and histological staining scores to determine the efficacy of MSC-EVs-based therapy, comparing treated rodents with untreated ones. BALF IL-4, BALF total cells, and BALF eosinophils were chosen as the primary outcomes, while airway hyper-responsiveness Penh values, BALF cytokines excluding IL-4, and histological staining scores were chosen as secondary outcomes.
RESULTS: A total of 19 eligible studies were included in the current systematic review, with 9 assessing BALF IL-4, 11 assessing BALF total cells, and 10 assessing BALF eosinophils. Pooled Hedges\' g (p-value) for each outcome was - 4.407 (< 0.001), -4.976 (< 0.001), and - 4.071 (< 0.001), showing that MSC-EVs therapy inhibits asthma pathology. Changes in secondary outcomes also indicated a reduction in inflammation, goblet cell hyperplasia, and airway hyper-responsiveness. Subgroup analyses did not reveal significant disparities between the type of rodents and administration routes, and meta-regressions were only significant for MSC-EVs source and dose in the IL-4 meta-analysis, and for administration frequency and time from the last challenge to sacrifice in the BALF total cell meta-analysis.
CONCLUSIONS: This review highlights the current pre-clinical evidence of MSC-EVs therapy for asthma and finds its application ameliorates multiple aspects of asthma\'s pathology. We further underline the importance of MSC-EVs source, dose, administration frequency, and timing on the therapeutic effect and warrant further investigation and clinical translation to assess the best treatment regimen and to gauge the efficacy of EV therapy in human asthma cases.
METHODS: A systematic search of electronic databases was performed. Meta-analyses were conducted on broncho-alveolar lavage fluid (BALF) cells and cytokines, as well as airway hyper-responsiveness Penh values and histological staining scores to determine the efficacy of MSC-EVs-based therapy, comparing treated rodents with untreated ones. BALF IL-4, BALF total cells, and BALF eosinophils were chosen as the primary outcomes, while airway hyper-responsiveness Penh values, BALF cytokines excluding IL-4, and histological staining scores were chosen as secondary outcomes.
RESULTS: A total of 19 eligible studies were included in the current systematic review, with 9 assessing BALF IL-4, 11 assessing BALF total cells, and 10 assessing BALF eosinophils. Pooled Hedges\' g (p-value) for each outcome was - 4.407 (< 0.001), -4.976 (< 0.001), and - 4.071 (< 0.001), showing that MSC-EVs therapy inhibits asthma pathology. Changes in secondary outcomes also indicated a reduction in inflammation, goblet cell hyperplasia, and airway hyper-responsiveness. Subgroup analyses did not reveal significant disparities between the type of rodents and administration routes, and meta-regressions were only significant for MSC-EVs source and dose in the IL-4 meta-analysis, and for administration frequency and time from the last challenge to sacrifice in the BALF total cell meta-analysis.
CONCLUSIONS: This review highlights the current pre-clinical evidence of MSC-EVs therapy for asthma and finds its application ameliorates multiple aspects of asthma\'s pathology. We further underline the importance of MSC-EVs source, dose, administration frequency, and timing on the therapeutic effect and warrant further investigation and clinical translation to assess the best treatment regimen and to gauge the efficacy of EV therapy in human asthma cases.
摘要：
背景：哮喘是一种常见疾病，以及多年来残疾的最主要原因之一。间充质干细胞衍生的细胞外囊泡（MSC-EV）已成为哮喘管理的有希望的途径。这项研究的目的是对临床前研究进行系统评价和荟萃分析，研究MSC-EV在哮喘小鼠模型中的治疗用途。
方法：对电子数据库进行系统检索。对支气管肺泡灌洗液(BALF)细胞和细胞因子进行Meta分析,以及气道高反应性Penh值和组织学染色评分，以确定基于MSC-EV的治疗的疗效，比较处理的啮齿动物与未处理的啮齿动物。BALFIL-4，BALF总细胞，选择BALF嗜酸性粒细胞作为主要结果，而气道高反应性Penh值，选择不包括IL-4的BALF细胞因子和组织学染色评分作为次要结果。
结果：本系统综述共纳入19项符合条件的研究，9评估BALFIL-4，11评估BALF总细胞，和10评估BALF嗜酸性粒细胞。每个结果的集合对冲（p值）为-4.407（<0.001），-4.976（<0.001），和-4.071（<0.001），显示MSC-EV治疗抑制哮喘病理。次要结局的变化也表明炎症的减少，杯状细胞增生,和气道高反应性。亚组分析没有发现啮齿动物类型和给药途径之间的显著差异，在IL-4荟萃分析中，meta回归仅对MSC-EV来源和剂量有意义，以及BALF总细胞荟萃分析中从最后一次攻击到处死的给药频率和时间。
结论：这篇综述强调了目前MSC-EV治疗哮喘的临床前证据，并发现其应用可以改善哮喘病理的多个方面。我们进一步强调MSC-EV来源的重要性，剂量,给药频率,以及治疗效果的时机，并需要进一步研究和临床翻译，以评估最佳治疗方案并评估EV治疗在人类哮喘病例中的疗效。
方法：对电子数据库进行系统检索。对支气管肺泡灌洗液(BALF)细胞和细胞因子进行Meta分析,以及气道高反应性Penh值和组织学染色评分，以确定基于MSC-EV的治疗的疗效，比较处理的啮齿动物与未处理的啮齿动物。BALFIL-4，BALF总细胞，选择BALF嗜酸性粒细胞作为主要结果，而气道高反应性Penh值，选择不包括IL-4的BALF细胞因子和组织学染色评分作为次要结果。
结果：本系统综述共纳入19项符合条件的研究，9评估BALFIL-4，11评估BALF总细胞，和10评估BALF嗜酸性粒细胞。每个结果的集合对冲（p值）为-4.407（<0.001），-4.976（<0.001），和-4.071（<0.001），显示MSC-EV治疗抑制哮喘病理。次要结局的变化也表明炎症的减少，杯状细胞增生,和气道高反应性。亚组分析没有发现啮齿动物类型和给药途径之间的显著差异，在IL-4荟萃分析中，meta回归仅对MSC-EV来源和剂量有意义，以及BALF总细胞荟萃分析中从最后一次攻击到处死的给药频率和时间。
结论：这篇综述强调了目前MSC-EV治疗哮喘的临床前证据，并发现其应用可以改善哮喘病理的多个方面。我们进一步强调MSC-EV来源的重要性，剂量,给药频率,以及治疗效果的时机，并需要进一步研究和临床翻译，以评估最佳治疗方案并评估EV治疗在人类哮喘病例中的疗效。
