A Human Single-Nuclei Atlas Reveals Novel Cell States during the Pseudoglandular-to-Canalicular Transition

Most of our knowledge of human lung development is derived from morphologic studies and extrapolations of the underlying molecular mechanisms from animal models. Here we describe developmental changes in human fetal lungs during the pseudoglandular and early canalicular period, detailing this critical but previously poorly described transition period. We report the cellular composition and cell-to-cell communication in a single-nuclei dataset from nine human fetal lungs between 14 and 19 weeks of gestation. We identified 9 main populations and 19 subpopulations, including the rare pulmonary neuroendocrine cells. For each population, marker genes were reported, and selected markers were validated. Enrichment analysis were performed to explore the potential molecular mechanisms and pathways within individual populations according to gestational age. Finally, cell-to-cell communication was studied using ligand-receptor analysis among the different cell types. General developmental pathways, as well as pathways involved in vasculogenesis, neurogenesis, and immune regulation, were identified. This study provides an important background to generate research hypotheses in projects studying normal or impaired lung development and help to validate surrogate models (e.g., lung organoids) to study human lung development.