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Am J Physiol Lung Cell Mol Physiol. 2017 Feb 1;312(2):L196-L207. doi: 10.1152/ajplung.00127.2016. Epub 2016 Dec 9.

Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes.

Author information

1
Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; gturcatel@chla.usc.edu.
2
Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.
3
Keck School of Medicine, University of Southern California, Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Division, Los Angeles, California.
4
Keck Graduate Institute, Claremont, California; and.
5
Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, Ostrow School of Dentistry, University of Southern California, Los Angeles, California.

Abstract

The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9Δ/Δ mutant embryos showed altered mRNA expression of various epithelial markers such as Pb1fa1, surfactant protein B (Sftpb), secretoglobulin, family 1A, member 1 (Scgb1a1), and trefoil factor 1 (Tff1). In vitro tracheal epithelial cell cultures confirmed that tracheal chondrocytes secrete factors that inhibit club cell differentiation. Whole gene expression profiling and ingenuity pathway analysis showed that the tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β) signaling pathways were significantly altered in the Sox9 mutant trachea. TNF-α and IFN-γ interfered with the differentiation of tracheal epithelial progenitor cells into mature epithelial cell types in vitro. Mesenchymal knockout of Tgf-β1 in vivo resulted in altered differentiation of the tracheal epithelium. Finally, mitochondrial enzymes involved in fat and glycogen metabolism, cytochrome c oxidase subunit VIIIb (Cox8b) and cytochrome c oxidase subunit VIIa polypeptide 1 (Cox7a1), were strongly upregulated in the Sox9 mutant trachea, resulting in increases in the number and size of glycogen storage vacuoles. Our results support a role for tracheal cartilage in modulation of the differentiation and metabolism and the expression of inflammatory-related genes in the tracheal epithelium by feeding into the TNF-α, IFN-γ, and TGF-β signaling pathways.

KEYWORDS:

Sox9; Tgf-β; basal cell; club cells; embryonic trachea

PMID:
27941074
PMCID:
PMC5336580
DOI:
10.1152/ajplung.00127.2016
[Indexed for MEDLINE]
Free PMC Article

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