Hypoxic Stem Cell-Derived Extracellular Vesicles for Cardiac Repair in Preclinical Animal Models of Myocardial Infarction: A Meta-Analysis

Given that the modification of stem cell-derived extracellular vesicles (EVs) can enhance their regenerative efficiency, an increasing number of studies pay attention to the therapeutic potential of hypoxic preconditioning of stem cell-derived EVs (Hypo-EVs) in cardiac repair. Our meta-analysis aims to evaluate the cardiac repair of Hypo-EVs in preclinical animal models of myocardial infarction (MI). We searched PubMed, EMBASE, and the Web of Science up to January 2021. The primary outcome was left ventricular ejection fraction (LVEF). The second outcomes were left ventricular fractional shortening (LVFS) and infarct size. Random-effects modeling was used to calculate pooled weighted mean differences (WMDs) and 95% confidence intervals (CIs). Nine studies satisfied the inclusion criteria. Compared with the model group, pooled analyses demonstrated that stem cell-derived EVs culturing in normal oxygen environment (Nor-EVs) can improve LVEF (WMD: 9.07, 95% CI: 6.76 to 11.38, I-2 = 80.7%), LVFS (WMD: 3.03, 95% CI: 0.79 to 5.27, I-2 = 86.3%), and reduce infarct size (WMD: -12.15, 95% CI: -19.12 to -5.18, I-2 = 96.8%). Compared with Nor-EVs, Hypo-EVs can improve LVEF (WMD: 5.11, 95% CI: 1.63 to 8.60, I-2 = 95%), LVFS (WMD: 6.54, 95% CI: 4.08 to 8.99, I-2 = 90.6%), and reduce infarct size (WMD: -7.42, 95% CI: -12.97 to -1.87, I-2 = 97.2%). These results suggest that Hypo-EVs could show more improvement than Nor-EVs therapy on cardiac repair in the preclinical MI animal model. However, future well-designed large animal studies might be necessary to clarify the methods and effects of Hypo-EVs therapy to help provide new ideas for future engineered EVs design.