Are all stem cells equal? Systematic review, evidence map, and meta-analyses of preclinical stem cell-based therapies for bronchopulmonary dysplasia

Abstract

Regenerative stem cell-based therapies for bronchopulmonary dysplasia (BPD), the most common preterm birth complication, demonstrate promise in animals. Failure to objectively appraise available preclinical data and identify knowledge gaps could jeopardize clinical translation. We performed a systematic review and network metaanalysis (NMA) of preclinical studies testing cell-based therapies in experimental neonatal lung injury. Fifty-three studies assessing 15 different cell-based therapies were identified: 35 studied the effects of mesenchymal stromal cells (MSCs) almost exclusively in hyperoxic rodent models of BPD. Exploratory NMAs, for select outcomes, suggest that MSCs are the most effective therapy. Although a broad range of promising cell-based therapies has been assessed, few head-to-head comparisons and unclear risk of bias exists. Successful clinical translation of cell-based therapies demands robust preclinical experimental design with appropriately blinded, randomized, and statistically powered studies, based on biological plausibility for a given cell product, in standardized models and endpoints with transparent reporting. K E Y W O R D Sanimal model, bronchopulmonary dysplasia, cell-based therapy, lung injury, network metaanalysis, preclinical, preterm birth, stem cells, systematic review, translation

MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges

“…Ongoing investigations within the baboon model of borderline viability are suitable to confirm the results from rodents and can help to determine functional improvements in more detail than mouse or rat models [ 120 ]. For these reasons, the just published meta-analysis was not able to provide final conclusions [ 69 ]. The robust comparison of different therapeutic approaches and the standardization of experimental settings are necessary prerogatives to dissolve these unanswered questions.…”

“…The studies in rodents were systematically reviewed in the meantime and came to the conclusion that MSC have a robust and overall positive effect on the pulmonary outcome. Beneficial effects were stated for initial and delayed MSC application and different sources, dosages and routes of exogenous MSC application as detailed above [ 65 , 69 ]. Benefits of MSC therapy were not restricted to the lung but also included reduced brain injury among others even when applied topically to the lung.…”

Recent advances in understanding and management of bronchopulmonary dysplasia

“…The precise mechanism by which they act is not completely known; however, it is believed that MSCs act primarily via a paracrine effect 63 . In a systematic review evaluating the various cell‐based therapies in preclinical BPD, MSCs were found to be the most efficacious among all interventions, although they were exclusively investigated in the rodent hyperoxia-exposed model of BPD 64 . Human umbilical cord tissue and cord blood have been identified as a potential source of MSCs and have been further explored as a feasible source of these cells and exosomes 65 , 66 .…”

Effects of mesenchymal stromal cell-conditioned media on measures of lung structure and function: a systematic review and meta-analysis of preclinical studies

“…This year, Augustine et al published a network meta-analysis comparing stem cell and cell-free therapies in preclinical measures of BPD. MSC-CdM had a similar effect size to MSCs regarding alveolarization (MSC SMD 1.71 vs. CdM SMD1.68), angiogenesis (SMD 2.24 vs. 1.79), and pulmonary remodeling (1.29 vs. 1.22) [ 39 ]. Similar to their results, this review showed that CdM had among the largest impact on measures of alveolarization and vasculogenesis, processes critical for appropriate lung healing, development, and function [ 40 ].…”