TY - JOUR
KW - Alveolar Epithelial Cells
KW - Cell Differentiation
KW - Cell Lineage
KW - Humans
KW - Infant, Newborn
KW - Lung
KW - NKX2.1
KW - NOTUM
KW - organoids
KW - Respiratory Tract Diseases
KW - WNT
KW - alveolar differentiation
KW - alveolar patterning
KW - distal tip
KW - human lung development
KW - organoids
KW - Stem cell
AU - Kyungtae Lim
AU - Alex P. A. Donovan
AU - Walfred Tang
AU - Dawei Sun
AU - Peng He
AU - J. Patrick Pett
AU - Sarah A. Teichmann
AU - John C. Marioni
AU - Kerstin B. Meyer
AU - Andrea H. Brand
AU - Emma L. Rawlins
AB - 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.
BT - Cell Stem Cell
DA - 2023-01-05
DO - 10.1016/j.stem.2022.11.013
IS - 1
LA - eng
N2 - 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.
PY - 2023
SP - 20
EP - 37.e9
T2 - Cell Stem Cell
TI - Organoid modeling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease
VL - 30
SN - 1875-9777
ER -