TGF-β activation impairs fibroblast ability to support adult lung epithelial progenitor cell organoid formation.

08:00 EDT 10th April 2019 | BioPortfolio

Summary of "TGF-β activation impairs fibroblast ability to support adult lung epithelial progenitor cell organoid formation."

Transforming growth factor-β (TGF-β)-induced fibroblast-to-myofibroblast differentiation contributes to remodeling in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, but whether this impacts the ability of fibroblasts to support lung epithelial repair remains little explored. We pre-treated human lung fibroblasts (primary [phFB] or MRC5 cells) with recombinant human TGF-β to induce myofibroblast differentiation, then co-cultured them with adult mouse lung EpCAM cells to investigate their capacity to support epithelial organoid formation in vitro. While control phFB and MRC5 lung fibroblasts supported organoid formation of mouse EpCAM cells, TGF-β-pre-treatment of both phFB and MRC5 impaired organoid-supporting ability. We performed RNA sequencing of TGF-β treated phFB, which revealed altered expression of key Wnt signaling pathway components and Wnt/β-catenin target genes, and modulated expression of secreted factors involved in mesenchymal-epithelial signaling. TGF-β profoundly skewed the transcriptional program induced by the Wnt/β-catenin activator CHIR99021 (CHIR). Supplementing organoid culture media recombinant hepatocyte growth factor (HGF) or fibroblast growth factor 7 (FGF7) promoted organoid formation when using TGF-β pre-treated fibroblasts. In conclusion, TGF-β-induced myofibroblast differentiation results in Wnt/β-catenin pathway skewing, and impairs fibroblast ability to support epithelial repair likely through multiple mechanisms including modulation of secreted growth factors.


Journal Details

This article was published in the following journal.

Name: American journal of physiology. Lung cellular and molecular physiology
ISSN: 1522-1504


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Medical and Biotech [MESH] Definitions

A fibroblast growth factor receptor that is found in two isoforms. One receptor isoform is found in the MESENCHYME and is activated by FIBROBLAST GROWTH FACTOR 2. A second isoform of fibroblast growth factor receptor 2 is found mainly in EPITHELIAL CELLS and is activated by FIBROBLAST GROWTH FACTOR 7 and FIBROBLAST GROWTH FACTOR 10. Mutation of the gene for fibroblast growth factor receptor 2 can result in APERT SYNDROME.

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A fibroblast growth factor that is a specific mitogen for EPITHELIAL CELLS. It binds a complex of HEPARAN SULFATE and FIBROBLAST GROWTH FACTOR RECEPTOR 2B.

Absence of air in the entire or part of a lung, such as an incompletely inflated neonate lung or a collapsed adult lung. Pulmonary atelectasis can be caused by airway obstruction, lung compression, fibrotic contraction, or other factors.

A fibroblast growth factor receptor that is mainly expressed in LUNG; KIDNEY; PANCREAS; and SPLEEN. It also plays an important role in SKELETAL MUSCLE development and can contribute to NEOPLASTIC CELL TRANSFORMATION.

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