Lung Injury in Preterm Neonates: The Role and Therapeutic Potential of Stem Cells

Continuous improvements in perinatal care have allowed the survival of ever more premature infants, making the task of protecting the extremely immature lung from injury increasingly challenging. Premature infants at risk of developing chronic lung disease or bronchopulmonary dysplasia (BPD) are now born at the late canalicular stage of lung development, just when the airways become juxtaposed to the lung vasculature and when gas-exchange becomes possible. Readily available strategies, including improved antenatal management (education, regionalization, steroids, and antibiotics), together with exogenous surfactant and exclusive/early noninvasive ventilatory support, will likely decrease the incidence/severity of BPD over the next few years. Nonetheless, because of the extreme immaturity of the developing lung, the extent to which disruption of lung growth after prematurity and neonatal management lead to an earlier or more aggravated decline in respiratory function in later life is a matter of concern. Consequently, much more needs to be learned about the mechanisms of lung development, injury, and repair. Recent insight into stem cell biology has sparked interest for stem cells to repair damaged organs. This review summarizes the exciting potential of stem cell-based therapies for lung diseases in general and BPD in particular. Antioxid. Redox Signal. 17, 1013–1040. I. Bronchopulmonary Dysplasia: Chronic Lung Disease for a Life Time? II. Pathophysiology of Lung Injury in Preterm Neonates A. Stages of lung organogenesis B. BPD: the impact of injury in an immature lung C. The multifactorial pathogenesis of BPD 1. Defective elastogenesis and extracellular matrix remodeling 2. Altered alveolar epithelial–mesenchymal interactions 3. Impaired development of lung microvasculature D. Oxidative stress: a distinct contributor to BPD evolution III. Stem Cells: Concepts and Applications A. Developmental potency of stem cells B. Classical versus nonclassical stem cell hierarchies C. Regulation of stem cell function D. Concept of stem cell replacement IV. Lung Stem Cells A. Lung epithelial stem/progenitor cells 1. Progenitor cells of the alveolar epithelium B. Lung mesenchymal progenitors V. Therapeutic Potential of Stem Cells to Prevent/Repair Lung Damage A. Mesenchymal stem cells B. Endothelial progenitor cells C. Embryonic stem cells D. Endogenous lung progenitors E. Paracrine effect of stem cells VI. BPD and Stem Cells A. Fate of stem/progenitor cells in BPD B. Cell therapy approaches for BPD 1. Mesenchymal stem cells 2. Human amniotic fluid stem cells 3. Endothelial progenitor cells 4. Human amnion epithelial cells VII. Summary and Remaining Challenges VIII. Conclusion