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Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis

Lookup NU author(s): Professor Andrew FisherORCiD


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© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Introduction Fibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling unmanipulated myofibroblasts within fibrotic foci in situ by laser capture microdissection. Methods The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an eigengene-based approach to identify transcriptional signatures, which correlate with fibrillar collagen gene expression. Results WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that transforming growth factor β1 (TGF-β1), RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene-edited cells demonstrated a key role for the TSC2/ RHEB axis in regulating TGF-β1-induced mechanistic target of rapamycin complex 1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts. Conclusion These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identify the TSC2/ RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.

Publication metadata

Author(s): Guillotin D, Taylor AR, Plate M, Mercer PF, Edwards LM, Haggart R, Miele G, McAnulty RJ, Maher TM, Hynds RE, Jamal-Hanjani M, Marshall RP, Fisher AJ, Blanchard AD, Chambers RC

Publication type: Article

Publication status: Published

Journal: Thorax

Year: 2021

Volume: 76

Issue: 1

Pages: 73-82

Print publication date: 15/12/2020

Online publication date: 19/11/2020

Acceptance date: 11/09/2020

ISSN (print): 0040-6376

ISSN (electronic): 1468-3296

Publisher: BMJ Publishing Group


DOI: 10.1136/thoraxjnl-2020-214902

PubMed id: 33214245


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