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Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC‐EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta‐research methods, we determined the effectiveness of MSC‐EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta‐analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC‐EVs markedly reduced lung injury (SMD ‐4.33, CI ‐5.73 to ‐2.92), vascular permeability (SMD ‐2.43, CI ‐3.05 to ‐1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC‐EVs (SMD ‐1.45, CI ‐2.08 to ‐0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD ‐4.16, CI ‐5.68 to ‐2.64) and hypertrophy (SMD ‐2.80, CI ‐3.68 to ‐1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC‐EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration: PROSPERO CRD42020145334 [ABSTRACT FROM AUTHOR]

Keywords: acute lung injury; acute respiratory distress syndrome; exosomes; extracellular vesicles; mesenchymal stem cell; microRNA-27a-3p EN acute lung injury acute respiratory distress syndrome exosomes extracellular vesicles mesenchymal stem cell microRNA-27a-3p 1095 1097 3 06/24/20 20200701 NES 200701 The first clinical trial involving mesenchymal stem cells (MSCs) was conducted in 1995 to investigate their feasibility of administration and safety profile. In preclinical animal models, MSC-EVs have been shown to polarize macrophages from the M1 pro-inflammatory to M2 anti-inflammatory phenotype, improve histological lung injury, reduce alveolar-capillary barrier permeability, and attenuate lung inflammation. In turn, EV therapies may overcome challenges that hamper the successful translation of live cell treatments including tumorigenesis, immunoreactivity, limited shelf-life, and batch-to-batch variability in cell viability and/or efficacy. [Extracted from the article]

Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P =.02; I 2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, –0.69; 95% CI, –1.15 to –0.22; P =.004; I 2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects. [ABSTRACT FROM AUTHOR]