Mesenchymal Stromal Cell Therapy in Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis of Preclinical Studies

Abstract

Extreme prematurity is the leading cause of death among children under 5 years of age. Currently, there is no treatment for bronchopulmonary dysplasia (BPD), the most common complication of extreme prematurity. Experimental studies in animal models of BPD suggest that mesenchymal stromal cells (MSCs) are lung protective. To date, no systematic review and meta-analysis has evaluated the preclinical evidence of this promising therapy. Our protocol was registered with Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies prior to searching MEDLINE (1946 to June 1, 2015), Embase (1947 to 2015 Week 22), Pubmed, Web of Science, and conference proceedings (1990 to present) for controlled comparative studies of neonatal animal models that received MSCs or cell free MSC-derived conditioned media (MSC-CM). Lung alveolarization was the primary outcome. We used random effects models for data analysis and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. We screened 990 citations; 25 met inclusion criteria. All used hyperoxia-exposed neonatal rodents to model BPD. MSCs significantly improved alveolarization (Standardized mean difference of -1.330, 95% confidence interval [CI -1.724, -0.94, I² 69%]), irrespective of timing of treatment, source, dose, or route of administration. MSCs also significantly ameliorated pulmonary hypertension, lung inflammation, fibrosis, angiogenesis, and apoptosis. Similarly, MSC-CM significantly improved alveolarization, angiogenesis, and pulmonary artery remodeling. MSCs, tested exclusively in hyperoxic rodent models of BPD, show significant therapeutic benefit. Unclear risk of bias and incomplete reporting in the primary studies highlights nonadherence to reporting standards. Overall, safety and efficacy in other species/large animal models may provide useful information for guiding the design of clinical trials. Stem Cells Translational Medicine 2017;6:2079-2093.

Keywords: Animal model; Lung injury; Meta-analysis; Preterm birth; Stem cells.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2009 flow diagram. Abbreviations: BPD, bronchopulmonary dysplasia; MSC, mesenchymal stromal cell.

Figure 2

Meta‐Analysis of all included studies for the primary outcome of alveolarization. Forest plot of therapeutic potential of (A) MSCs and (B) MSC‐Conditioned media in animal model of BPD for the primary outcome of alveolarization. Black squares indicates the actual effect size of primary/individual studies. Red diamond indicates the overall or average effect size of all the primary studies. Abbreviations: MSC, mesenchymal stromal cell; SMD, standardized mean difference.

Figure 3

Funnel plot. Blue circles indicate studies included in the meta‐analysis for the primary outcome of alveolarization. Red circles suggest potentially missing studies for the same outcome.

Figure 4

Subgroup analyses of MSCs in animal model of bronchopulmonary dysplasia for the primary outcome of alveolarization. Abbreviations: MSC, mesenchymal stromal cells; SMD, standardized mean difference.