Bidirectional epithelial–mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

• DOI: 10.1016/j.jbc.2021.101096
• Publication Date: 2021-08-18T15:04:53Z
• Authors: Liudi Yao; Yilu Zhou; Juanjuan Li; Leanne Wickens; Franco Conforti; Anna Rattu; Fathima Maneesha ...; Aiman Alzetani; Ben G. Marshall; Sophie V. Fletcher; David Hancock; Tim Wallis; Julian Downward; Rob M. Ewing; Luca Richeldi; Paul Skipp; Donna E. Davies; Mark G. Jones; Yihua Wang
• Keywords: TGF-β; Male; Model organisms; 0301 basic medicine; Epithelial-Mesenchymal Transition; EGFR; Pulmonary Fibrosis; Primary Cell Culture; 610; Gene Expression; epithelial–mesenchymal transition; 12. Responsible consumption; Signalling & Oncogenes; 03 medical and health sciences; Cell Movement; Transforming Growth Factor beta; ZEB1; Humans; Lung; Chemical Biology & High Throughput; 0303 health sciences; pulmonary fibrosis; 9. Industry and infrastructure; Zinc Finger E-box-Binding Homeobox 1; SPARC; Epithelial Cells; Fibroblasts; Tumour Biology; Fibrosis; Idiopathic Pulmonary Fibrosis; Extracellular Matrix; Tissue Plasminogen Activator; Female; Genetics & Genomics; RAS; Research Article

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts via paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein, SPARC, which may signal via the epithelial growth factor receptor (EGFR) via EGF-like (EGFL) repeats. Together, these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.