Meta-Analysis of the Therapeutic Effects of Stem Cell-Derived Extracellular Vesicles in Rodent Models of Hemorrhagic Stroke

Abstract

Background: Stem cell-derived extracellular vesicles (SCEVs) have emerged as a potential therapy for hemorrhagic stroke. However, their effects are not fully understood. The aim of this study was to comprehensively evaluate the effects of SCEVs therapy in rodent models of hemorrhagic stroke, including subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH).

Materials and methods: We conducted a comprehensive search of PubMed, EMBASE, and Web of Science until May 2023 to identify studies investigating the effects of SCEVs therapy in rodent models of ICH. The functional outcomes were assessed using neurobehavioral scores. Standardized mean differences (SMDs) and confidence intervals (CIs) were calculated using a random-effects model. Three authors independently screened the articles based on inclusion and exclusion criteria. All statistical analyses were performed using Revman 5.3 and Stata 17.0.

Results: Twelve studies published between 2018 and 2023 met the inclusion criteria. Our results showed that SCEVs therapy improved neurobehavioral scores in the rodent SAH model (SMD = -3.49, 95% CI: -4.23 to -2.75; p < 0.001). Additionally, SCEVs therapy improved the chronic neurobehavioral scores of the rodent ICH model (SMD = 2.38, 95% CI: 0.36-4.40; p=0.02) but did not have a significant impact on neurobehavioral scores in the acute and subacute phases. Significant heterogeneity was observed among the studies, and further stratification and sensitivity analyses failed to identify the source of heterogeneity.

Conclusions: Our findings suggest that SCEVs therapy may improve neurofunctional behavior after hemorrhagic stroke and provide important insights into the design of preclinical trials.

Figure 1

Flowchart of the enrolled studies on SCEVs therapy in rodents with hemorrhagic stroke.

Figure 2

Forest plot showing the impact of SCEVs therapy on neurobehavioral scores in SAH, compared with controls. 95% CI: 95% confidence interval.

Figure 3

Forest plot showing the impact of SCEVs therapy on neurobehavioral scores in ICH, compared with controls: (a) acute stage (1−3 days); (b) subacute stage (7−14 days); (c) chronic stage (28−35 days). 95% CI: 95% confidence interval.

Figure 4

Sensitivity-analysis results of SAH.

Figure 5

Sensitivity-analysis results of ICH: (a) acute stage (1−3 days); (b) subacute stage (7−14 days); (c) chronic stage (28−35 days).

Figure 6

Publication-bias analysis results of SAH: (a) funnel plots for neurobehavioral scores; (b) trim-and-fill method was used to evaluate the missing studies in neurobehavioral scores.