biostudies-literatureLim KMinistry of EducationCancer Research UKBiogenMedical Research CouncilAllen InstituteNational Research Foundation of KoreaRoyal SocietyWellcome TrustUniversity of Cambridge20-37.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618456biostudies-literatureUnknown30(1)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 maturatioCell stem cellOrganoid modeling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease.PMC7618456206194103792109146MR/S035907/1MR/P009581/1103792/Z/14/Z109146/Z/15/ZWT206194203144MR/R006237/1203144/Z/16/Z2252212018R1A6A3A03012122WT211276/Z/18/ZC6946/A24843Pett JPMeyer KBBrand AHSun DLim KMarioni JCTang WDonovan APARawlins ELTeichmann SAHe PfalseOrganoid 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 maturatio2023-01-01T00:00:00Z2023 Jan2026-05-26T11:07:46.62Z2026-05-24T03:12:08.705ZS-EPMC76184563649378010.1016/j.stem.2022.11.013