Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

Abstract While animal models have provided key insights into conserved mechanisms of how the lung forms during development, human-specific developmental mechanisms are not always captured. To fully appreciate how developmental defects and disease states alter the function of the lungs, studies in human lung models are important. Here, we sequenced >150,000 single single-cells from 19 healthy human fetal lung tissues from gestational weeks 10-19 and identified at least 58 unique cell types/states contributing to the developing lung. We captured novel dynamic developmental trajectories from various progenitor cells that give rise to ciliated and pulmonary neuroendocrine cells. We also identified four CFTR-expressing progenitor cell types and pinpointed the temporal emergence of these cell types. These developmental dynamics reveal broader epithelial cell plasticity and novel lineage hierarchies that were not previously reported. Combined with spatial transcriptomics, we identified both cell autonomous and non-cell autonomous signalling pathways that may dictate the temporal and spatial emergence of cell lineages. Finally, we showed that human pluripotent stem cell¬-derived fetal lung models capture cell lineage trajectories specifically through CFTR-expressing progenitor cells, that were also observed in the native fetal tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development.