Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts

Erin Joanne Walker; Deborah Heydet; Timothy Veldre; Reena Ghildyal

doi:10.1038/s41598-019-56955-1

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Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts

Journal article

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Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts

Erin Joanne Walker, Deborah Heydet, Timothy Veldre and Reena Ghildyal

Scientific reports, Vol.9, pp.1-14

30/12/2019

DOI: https://doi.org/10.1038/s41598-019-56955-1

PMCID: PMC6937312

PMID: 31889146

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Abstract

Biomarkers

Cell Differentiation

Cells, Cultured

Fibroblasts - cytology

Fibroblasts - metabolism

Gene Expression Profiling

Humans

Myofibroblasts - cytology

Myofibroblasts - metabolism

Signal Transduction

Transcriptome

Transforming Growth Factor beta - metabolism

Experimental models of disease

Cellular signalling networks

Asthma is the most common chronic lung disease in children and young adults worldwide. Airway remodelling (including increased fibroblasts and myofibroblasts in airway walls due to chronic inflammation) differentiates asthmatic from non-asthmatic airways. The increase in airway fibroblasts and myofibroblasts occurs via epithelial to mesenchymal transition (EMT) where epithelial cells lose their tight junctions and are transdifferentiated to mesenchymal cells, with further increases in myofibroblasts occurring via fibroblast-myofibroblast transition (FMT). Transforming growth factor (TGF)-β is the central EMT- and FMT-inducing cytokine. In this study, we have used next generation sequencing to delineate the changes in the transcriptome induced by TGF-β treatment of WI-38 airway fibroblasts in both the short term and after differentiation into myofibroblasts, to gain an understanding of the contribution of TGF-β induced transdifferentiation to the asthmatic phenotype. The data obtained from RNAseq analysis was confirmed by quantitative PCR (qPCR) and protein expression investigated by western blotting. As expected, we found that genes coding for intermediates in the TGF-β signalling pathways (SMADs) were differentially expressed after TGF-β treatment, SMAD2 being upregulated and SMAD3 being downregulated as expected. Further, genes involved in cytoskeletal pathways (FN1, LAMA, ITGB1) were upregulated in myofibroblasts compared to fibroblasts. Importantly, genes that were previously shown to be changed in asthmatic lungs (ADAMTS1, DSP, TIMPs, MMPs) were similarly differentially expressed in myofibroblasts, strongly suggesting that TGF-β mediated differentiation of fibroblasts to myofibroblasts may underlie important changes in the asthmatic airway. We also identified new intermediates of signalling pathways (PKB, PTEN) that are changed in myofibroblasts compared to fibroblasts. We have found a significant number of genes that are altered after TGF-β induced transdifferentiation of WI-38 fibroblasts into myofibroblasts, many of which were expected or predicted. We also identified novel genes and pathways that were affected after TGF-β treatment, suggesting additional pathways are activated during the transition between fibroblasts and myofibroblasts and may contribute to the asthma phenotype.

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Title: Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts
Creators: Erin Joanne Walker - University of Canberra
Deborah Heydet - University of Canberra
Timothy Veldre - University of Canberra
Reena Ghildyal - University of Canberra
Publication Details: Scientific reports, Vol.9, pp.1-14
Publisher: Nature Publishing Group
Identifiers: 991013035747302368
Copyright: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2019
Academic Unit: National Centre for Naturopathic Medicine
Language: English
Resource Type: Journal article

Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts

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