Modeling Lung Cell Development Using Human Pluripotent Stem Cells

Human PSC (hPSC) differentiations can capture developmental phenotypes and processes and are useful for studying fundamental biological mechanisms driving tissue morphogenesis and cell lineage development. Here, we show for the first time the temporal development of lung cell lineages using hPSC that model developmental milestones observed in primary tissue, the generation of renewable fetal lung epithelial organoids, and the functional utility of the lung models at different differentiation stages for Cystic fibrosis disease modeling. We first show the presence of hPSC-derived lung progenitor cells reminiscent of early trimester lung development and can capture a population enriched with basal stem cells that generates renewable airway organoids. Maturation and polarization in air liquid interface (ALI) generates additional epithelial cell lineages found in adult lung tissues including pulmonary neuroendocrine, brush, mature basal, ciliated and secretory cell types. Finally, pseudotime analysis of the integrated datasets from the fetal and ALI stages reveal the developmental trajectories of the cells as they emerge during differentiation. Overall, hPSC differentiation can capture aspects of human lung development and potentially provide important insight into congenital causes of diseases.