Stem cells and bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity mainly affecting preterm infants that are born at 24–28 weeks of gestation. Surfactant therapy, antenatal steroids and incremental improvements in perinatal care have allowed survival of even more immature infants, but there is still no specific treatment for BPD. Recent advances in our understanding of stem cells offer the possibility for cell-based treatment for intractable diseases, including BPD. This review summarizes the recent progress and challenges of stem cell-based therapies for lung diseases, with a focus on BPD.
Damage or depletion of epithelial and/or vascular progenitors in the developing lung are likely to contribute to the pathogenesis of BPD. Baker et al. observed that cord blood of preterm infants yielded higher numbers of endothelial colony-forming cells (ECFCs) compared to term infants; however, cells from the former group were relatively more sensitive to oxygen in vitro. Other studies reported that ECFCs were lower in numbers in cord blood of preterm infants who subsequently developed BPD. These observations suggest an oxygen-induced depletion of vessel-forming progenitors. Given the importance of lung vasculature in lung development, injury and repair, this could be a possible mechanism underlying arrested lung vascular growth in BPD.
Recent reports have demonstrated the benefits of stem cell therapy in animal models of oxygen-induced BPD. Intravenous or intratracheal delivery of bone marrow-derived mesenchymal stem cells (MSCs) mitigated inflammation, prevented lung vascular and alveolar damage, and improved exercise tolerance and survival. In addition, MSCs from human cord blood prevented alveolar growth arrest and alleviated fibrotic changes in the lungs of oxygen-challenged neonatal rats. On these bases, MSCs may exert a therapeutic benefit via a paracrine mechanism, which could be further enhanced by ex vivo preconditioning of MSCs.
The observed depletion of circulating and lung resident endothelial progenitor cells (EPCs) in BPD together with beneficial vascular growth factor therapy demonstrated in experimental BPD models suggests a therapeutic potential of exogenous EPC supplementation. Accordingly, oxygen-exposed newborn mice treated with bone marrow-derived angiogenic cells showed almost complete restoration of lung structure.
In summary, studies from several laboratories indicate that a variety of stem cells prevent and/or regenerate oxygen-induced lung damage in neonatal rodents. However, many hurdles remain to be overcome before safe translation of cell-based therapies in newborns can be achieved. Strong emphasis must be placed on developing and standardizing techniques for stem/progenitor cell definition, isolation, expansion and therapeutic administration.
Additional prerequisites for the potential clinical application of cell-based therapies for newborns suffering from BPD include: identifying the best 'reparative cell(s)' and their source, understanding alternate mechanisms of action beyond cell replacement and assessing short- and long-term efficacy and safety in rigorously well-designed preclinical studies.

Top