Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis.
Date
2021-09-01ICR Author
Author
Yao, L
Zhou, Y
Li, J
Wickens, L
Conforti, F
Rattu, A
Ibrahim, FM
Alzetani, A
Marshall, BG
Fletcher, SV
Hancock, D
Wallis, T
Downward, J
Ewing, RM
Richeldi, L
Skipp, P
Davies, DE
Jones, MG
Wang, Y
Type
Journal Article
Metadata
Show full item recordAbstract
Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 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 zinc finger E-box-binding homeobox 1-mediated epithelial-mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-β-induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial-mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1-tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor-like repeats. Together, these data identify that aberrant bidirectional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.
Collections
Subject
EGFR
RAS
SPARC
TGF-β
ZEB1
epithelial–mesenchymal transition
pulmonary fibrosis
Cell Movement
Epithelial Cells
Epithelial-Mesenchymal Transition
Extracellular Matrix
Female
Fibroblasts
Fibrosis
Humans
Idiopathic Pulmonary Fibrosis
Lung
Male
Primary Cell Culture
Pulmonary Fibrosis
Tissue Plasminogen Activator
Transforming Growth Factor beta
Zinc Finger E-box-Binding Homeobox 1
Research team
Lung Cancer Group
Language
eng
Date accepted
2021-08-17
License start date
2021-09-01
Citation
Journal of Biological Chemistry, 2021, 297 (3), pp. 101096 -
Publisher
ELSEVIER
Except where otherwise noted, this item's license is described
as
http://creativecommons.org/licenses/by/4.0/
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