FGF10 maintains distal lung bud epithelium and excessive signaling leads to progenitor state arrest, distalization, and goblet cell metaplasia.
BACKGROUND
Interaction with the surrounding mesenchyme is necessary for development of endodermal organs, and Fibroblast growth factors have recently emerged as mesenchymal-expressed morphogens that direct endodermal morphogenesis. The fibroblast growth factor 10 (Fgf10) null mouse is characterized by the absence of lung bud development. Previous studies have shown that this requirement for Fgf10 is due in part to its role as a chemotactic factor during branching morphogenesis. In other endodermal organs Fgf10 also plays a role in regulating differentiation.


RESULTS
Through gain-of-function analysis, we here find that FGF10 inhibits differentiation of the lung epithelium and promotes distalization of the embryonic lung. Ectopic expression of FGF10 in the lung epithelium caused impaired lung development and perinatal lethality in a transgenic mouse model. Lung lobes were enlarged due to increased interlobular distance and hyperplasia of the airway epithelium. Differentiation of bronchial and alveolar cell lineages was inhibited. The transgenic epithelium consisted predominantly of proliferating progenitor-like cells expressing Pro-surfactant protein C, TTF1, PEA3 and Clusterin similarly to immature distal tip cells. Strikingly, goblet cells developed within this arrested epithelium leading to goblet cell hyperplasia.


CONCLUSIONS
We conclude that FGF10 inhibits terminal differentiation in the embryonic lung and maintains the distal epithelium, and that excessive levels of FGF10 leads to metaplastic differentiation of goblet cells similar to that seen in chronic inflammatory diseases.
Nyeng
Pia
P
Cleveland Clinic Foundation, Lerner Research Institute, Stem Cell Biology and Regenerative Medicine, 9500 Euclid Avenue, Cleveland Ohio, USA. nyengp@ccf.org
Norgaard
Gitte A
GA
Kobberup
Sune
S
Jensen
Jan
J
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D051526:Fibroblast Growth Factor 10 / Q000096:biosynthesis*; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006965:Hyperplasia; D008168:Lung / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009130:Muscle, Smooth / Q000196:embryology / Q000473:pathology; D011650:Pulmonary Alveoli / Q000196:embryology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis; D051176:beta Catenin / Q000096:biosynthesis
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D018398:Homeodomain Proteins; D015534:Trans-Activators; D051176:beta Catenin; C084010:pancreatic and duodenal homeobox 1 protein