Generation and regeneration of the neonatal lung is critical in the treatment of pediatric pulmonary hypertension (PH) associated with developmental lung disease. In order to generate diverse lung lineages, multipotent lung progenitor cells must simultaneously express genes for multiple specific lineages. For progenitor cell commitment to occur, cell-specific transcriptional networks must be activated, and simultaneously, alternative fate gene expression must also be switched off, processes that are currently poorly understood for alveolar epithelial cell fate. Formation of the alveolus, the functional unit of gas exchange in the lung, entails appropriate differentiation of the alveolar epithelium into a type 1 (AT1) or type 2 (AT2) alveolar epithelial cell and maturation of a juxtaposed capillary plexus. Of note, disruption of this process, results in developmental lung disease such as bronchopulmonary dysplasia, a disease frequently associated with PH. Therefore, and understanding of the mechanisms of alveolar epithelial cell fate may provide critical insight into reinitiating lung growth in developmental lung disease and PH.
Recently, we prospectively identified a pool of AT2 cells that primarily contributes to lung growth and regeneration. Separately, we have also determined that commitment to the alveolar epithelial lineage occurs much earlier in development than previously recognized. Furthermore, we have demonstrated that this cell fate is regulated by a transcriptional repressor, called Hopx, and the activating transcription factor, b-catenin. These preliminary results suggest a new paradigm for lung alveolar development, where alveolar epithelial cells are specified in the early stages of lung development. In addition, these findings suggest an additional layer of regulation in switching off alternative fate gene expression in cell commitment. Unraveling these mechanisms will provide critical insight into reinitiating lung growth in developmental lung disease. Similarly, understanding the regulation and coordination of alveolar epithelial plasticity will help drive new potential therapies in neonatal and adult lung regeneration.