Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

Abstract

Objectives: To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects.

Methods: A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints.

Results: Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral > intra-arterial > IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate > rat > mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ≥ 24 hours poststroke; results were overall very similar.

Conclusions: In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.

Figure 1. MSC effect size across all studies

Forest plot shows mean effect size and 95% CI for (A) mNSS, (B) infarct volume reduction, (C) adhesive removal test, and (D) rotarod test. Values for effect size were very large and highly significant and were robust across numerous variables such as (A) route of MSC administration and (B) time of MSC administration after stroke. CI = confidence interval; hd = higher-dose group; IA = intra-arterial; IC = intracerebral; ld = lower-dose group; mNSS = modified Neurological Severity Score; MSC = mesenchymal stromal cell; P2 = 2 passages in culture; P6 = 6 passages in culture.

Figure 2. Clinical correlates of effect size among studies introducing MSCs in the restorative therapy time window

For the studies that introduced MSCs ≥24 hours poststroke: (A) higher Quality Score was associated with greater behavioral effects of MSCs (r = 0.42, p < 0.04). (B) Lower MSC doses were associated with greater behavioral effects (r = −0.58, p < 0.002). (C) The effect size of MSCs on infarct volume reduction varied in relation to the species being studied and was highest in subhuman primates (mean ± SEM, p < 0.03). (D) The effect size of MSC therapy for the rotarod test varied in relation to time of MSC administration relative to stroke; effect sizes were higher in studies with later time of MSC introduction (r = 0.77, p < 0.004). Values for effect size are Hedges' g. MSC = mesenchymal stromal cell.