Organoid modeling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease

Variation in lung alveolar development is strongly linked to disease susceptibility. However, underlying cellular and molecular mechanisms are difficult to study in humans. We have identified an alveolar-fated epithelial progenitor in human fetal lungs, which we grow as self-organizing organoids that model key aspects of cell lineage commitment. Using this system, we have functionally validated cell-cell interactions in the developing human alveolar niche, showing that Wnt signaling from differentiating fibroblasts promotes alveolar-type-2 cell identity, whereas myofibroblasts secrete the Wnt inhibitor, NOTUM, providing spatial patterning. We identify a Wnt-NKX2.1 axis controlling alveolar differentiation. Moreover, we show that differential binding of NKX2.1 coordinates alveolar maturation, allowing us to model the effects of human genetic variation in NKX2.1 on alveolar differentiation. Our organoid system recapitulates key aspects of human fetal lung stem cell biology allowing mechanistic experiments to determine the cellular and molecular regulation of human development and disease. [Display omitted] •Human fetal lung tip progenitor cells commit to alveolar fate from 15 pcw in vivo•Late-stage tip-derived organoids readily differentiated to mature cell fates•NOTUM+ myofibroblasts spatially pattern differentiating human alveolar-type-2 cells•Lineage-determining TFs facilitate organoid modeling of neonatal lung disease Lim and colleagues identify the timing of alveolar-fate specification in human fetal lungs. Their stage-specific organoids allow functional analysis of mechanisms controlling fate maintenance and differentiation in the developing alveolar niche, facilitating the modeling of neonatal lung disease.