Dataset Information

Impaired FGF10 Signaling and Epithelial Development in Experimental Lung Hypoplasia With Esophageal Atresia.

ABSTRACT: Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often experience persistent respiratory tract disease. In experimental models, doxorubicin-induced developmental lung abnormalities may result from downregulation of branching morphogenesis factor fibroblast growth factor (Fgf10). This study investigated the temporospatial expression of Fgf10 pathway components and lung epithelial factors in an doxorubicin-induced EA-TEF model by quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting. Epigenetic regulation of gene expression by histone deacetylation was also investigated. Bone morphogenetic protein (Bmp) 4 and Cathepsin H (Ctsh), downstream targets of Fgf10, were significantly downregulated in the EA-TEF model during the saccular stage, consistent with Fgf10 expression. The developmental expression pattern of P2x7 receptor (ATI-cell marker), Sftpa, and Sftpb in lung epithelial cells was not affected. Sftpc (ATII-cell Marker) and Scgb1a1 (Clara cell marker) were significantly downregulated at the canalicular stage. Meanwhile, histone deacetylase (Hdac) 1 was upregulated and subsequently decreased acetylation of histone H3 Lys56 in the EA-TEF model, which returned to a normal level at the saccular stage. In conclusion, disturbed molecular signaling involving Fgf10/Ctsh was associated with impaired airway branching and epithelial cell development in lung morphogenesis, as evidenced by downregulated Sftpc and Scgb1a1 protein expression. The influence of Hdac1 activity on gene and protein expression in lung epithelial cells deserves further study.

SUBMITTER: Wang J

PROVIDER: S-EPMC5921531 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Impaired FGF10 Signaling and Epithelial Development in Experimental Lung Hypoplasia With Esophageal Atresia.

Wang Jun J Liu Hao H Gao Linlin L Liu Xiaomei X

Frontiers in pediatrics 20180420

Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often experience persistent respiratory tract disease. In experimental models, doxorubicin-induced developmental lung abnormalities may result from downregulation of branching morphogenesis factor fibroblast growth factor (Fgf10). This study investigated the temporospatial expression of Fgf10 pathway components and lung epithelial factors in an doxorubicin-induced EA-TEF model by quantitative polymerase chain reaction, imm ...[more]

PMID: 29732364

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Project description:The existence during mouse lung development of an embryonic stage temporally and functionally distinct from the subsequent pseudoglandular stage has been proposed but never demonstrated; while studies in human embryonic lung tissue fail to recapitulate the molecular control of branching found in mice. Lung development in mice starts officially at embryonic day (E) 9.5 when on the ventral side of the primary foregut tube, both the trachea and the two primary lung buds emerge and elongate to form a completely separate structure from the foregut by E10. In the subsequent 6 days, the primary lung buds undergo an intense process of branching to form a ramified tree by E16.5. We used transgenic mice allowing to transiently inhibit endogenous fibroblast growth factor 10 (Fgf10) activity in mutant embryos at E9, E9.5, and E11 upon intraperitoneal exposure to doxycycline and examined the resulting lung phenotype at later developmental stages. We also determined using gene arrays the transcriptomic response of flow cytometry-isolated human alveolar epithelial progenitor cells derived from hESC or hiPSC, grown in vitro for 12 or 24 h, in the presence or absence of recombinant FGF10. Following injection at E9, the corresponding mutant lungs at E18.5 appear almost normal in size and shape but close up examination indicate failure of the right lung to undergo lobar septation. At E9.5, the lungs are slightly hypoplastic but display normal differentiation and functionality. However, at E11, the lungs show impaired branching and are no longer functional. Using gene array data, we report only a partial overlap between human and mouse in the genes previously shown to be regulated by Fgf10 at E12.5. This study supports the existence of an embryonic stage of lung development where Fgf10 signaling does not play a function in the branching process but rather in lobar septation. It also posits that functional comparisons between mouse and human organogenesis must account for these distinct stages.

Dataset Information

Impaired FGF10 Signaling and Epithelial Development in Experimental Lung Hypoplasia With Esophageal Atresia.

Publications

Impaired FGF10 Signaling and Epithelial Development in Experimental Lung Hypoplasia With Esophageal Atresia.

Similar Datasets

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