FGF Signaling Directs AT2 Cell Fate and Morphogenesis in Alveolar Organoids (PRJCA050009)
Alveolar organoids serve as pivotal in vitro models for investigating pulmonary development, homeostasis, and regeneration. Using two distinct alveolar organoid media (AOM) to culture alveolar type-2 epithelial cells (AT2), we generated divergent organoid populations. Systematic comparison revealed that AOM1-derived organoids comprised AT2 cells, pre-alveolar type-1 transitional state (PATS) cells, and alveolar type-1 epithelial cells (AT1). In contrast, AOM2-derived organoids contained AT2 and PATS populations but lacked AT1 cells. AOM2-derived organoids demonstrated enhanced clonogenicity, greater proliferative capacity, and larger diameters than AOM1-derived counterparts. Leveraging these models, we delineated how fibroblast growth factor (FGF) signaling regulates AT2 fate determination and morphogenesis. FGF10 promoted organoid formation efficiency via JAK-STAT and PI3K-AKT pathways, while FGF7 drove proliferative expansion through DNA replication and cell cycle progression pathways. This work establishes that media composition critically dictates cellular diversity in alveolar organoids and reveals functionally distinct roles for FGF ligands in orchestrating AT2 cell fate specification and morphogenesis in vitro.