Schematic representation of fetal stem cells and iPSC-derived lung organoids. (A) Bud tip progenitor cells obtained from fetal lung tissue can be differentiated into alveolar and airway organoids. Activation of WNT pathway signaling leads to the formation of alveolar organoids containing SFTPC⁺HOPX⁺ AECs, while dual SMAD activation and inhibition lead to the development of airway organoids composed of basal, club, goblet, and multiciliated cells (24, 51). Stimulation of bud tip progenitors with ATRA and FGF-7 gives rise to alveolar-like or airway-like organoids depending on the coculture with either LIFR⁺ or LIFR^– lung mesenchymal cells (52). (B) Lung organoids derived from iPSCs are generally generated from NKX2-1 lung progenitor cells. For this purpose, iPSCs are differentiated into definitive endoderm and polarized into anterior foregut endoderm before being differentiated into lung progenitors. Dual SMAD activation and inhibition of NKX2-1 or organoid-derived NKX2-1⁺TP63⁺ progenitor cells result in the formation of airway organoids containing basal, club, goblet, and multiciliated cells and, in some conditions, SYN⁺ neuroendocrine cells (27, 28). In contrast, stimulation of lung progenitor cells with DCI, FGF, and CHIR leads to the formation of alveolar organoids comprising AEC1s and AEC2s (27, 61). In contrast, lung organoids comprising both alveolar-like cell types and airway-like cell types can be generated by addition of FGF-10 (25). Stimulation of lung progenitor cells with ATRA, FGF-7, and CHIR results in the generation of bud tip organoids containing NKX2-1⁺ lung progenitor cells, AEC2s, and club and goblet cells (25).