Regulation of Progenitor Cell Plasticity in Lung Development and Disease-Repair

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ABSTRACT Despite much progress in the field of lung biology and pulmonary medicine, a major gap of knowledge remains in the lack of a broader understanding of the composition and regulation of the lung stem cell compartment and its behavior in disease and regeneration-repair. Recent studies bring an additional complexity to the scenario, as they describe injured lung cells in a plastic intermediate state at the crossroad between resolution to a normal state and abnormal failed repair of the lung. Little is known about the origin and regulation of these intermediate cell states and their relationship to the programs that regulate cell fate decisions in the developing lung. There has been also an increasing need to have a better understanding of the developmental and repair programs in human lung progenitors, their impact in perinatal conditions and potential link to adult chronic diseases. Here we propose to address these gaps of knowledge in this research proposal by: a) exploring new observations that identify a similar transitional state in developing lung epithelial progenitors, to investigate mechanisms of cell plasticity that balances the cell fate program of airways and alveoli and prevents aberrant lung growth, b) investigating the developmental origins of dysanaptic lung growth and its link to COPD by integrating information from genetic-epidemiologic cohorts with that from organoid and mouse genetic models, c) investigating the impact of fetal–intrauterine environment in the control of plasticity and maturation of human neonatal airway progenitor cells. Results from these studies will open new perspectives in our understanding of the mechanisms of how cell fate decisions are regulated in development and disease- repair providing insights for future therapeutic interventions.