02325nas a2200469   4500000000100000000000100001008004100002260001500043653003000058653002500088653001700113653001100130653002000141653000900161653001100170653001000181653001400191653003100205653000800236653002900244653002400273653001500297653002700312653001400339653001400353100001700367700002300384700001700407700001400424700001200438700002000450700002300470700002000493700002100513700002000534700002000554245013900574300001300713490000700726520110800733022001401841       2023                            d  c2023-01-0510aAlveolar Epithelial Cells10aCell Differentiation10aCell Lineage10aHumans10aInfant, Newborn10aLung10aNKX2.110aNOTUM10aorganoids10aRespiratory Tract Diseases10aWNT10aalveolar differentiation10aalveolar patterning10adistal tip10ahuman lung development10aorganoids10aStem cell1 aKyungtae Lim1 aAlex P. A. Donovan1 aWalfred Tang1 aDawei Sun1 aPeng He1 aJ. Patrick Pett1 aSarah A. Teichmann1 aJohn C. Marioni1 aKerstin B. Meyer1 aAndrea H. Brand1 aEmma L. Rawlins00aOrganoid modeling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease  a20-37.e90 v303 aVariation 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.  a1875-9777