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Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis

Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis
Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis

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.

0021-9258
Yao, Liudi
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Zhou, Yilu
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Li, Juanjuan
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Wickens, Leanne
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Conforti, Franco
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Rattu, Anna
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Ibrahim, Fathima M
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Alzetani, Aiman
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Marshall, Benjamin
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Fletcher, Sophie V.
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Hancock, David
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Wallis, Timothy
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Downward, Julian
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Ewing, Robert
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Richeldi, Luca
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Skipp, Paul
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Davies, Donna
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Jones, Mark
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Wang, Yihua
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Yao, Liudi
3c9ce766-5334-49f7-9517-c4dc2013f933
Zhou, Yilu
1878565d-39e6-467d-a027-7320bf4cdaf2
Li, Juanjuan
7888cf96-2102-4b8c-b719-5dd71f4c359d
Wickens, Leanne
82651539-c81b-40e1-bbf0-9f3e0f66ee52
Conforti, Franco
28bf123c-e42a-4fb5-8b26-f79e1095c586
Rattu, Anna
ea310926-604d-4307-9843-0bf7b30240e2
Ibrahim, Fathima M
b1436b35-1117-4a45-ab18-6235af2a3f6c
Alzetani, Aiman
6dc94b31-f7c1-4341-a805-5c8e8d21dbde
Marshall, Benjamin
9abf382c-977f-459c-9b91-5ed8cbf2284f
Fletcher, Sophie V.
29363f9b-517e-4303-9cdf-941461520fa5
Hancock, David
142ef93e-e0b9-4ec7-abab-76680f3f0e8c
Wallis, Timothy
cf385c2a-ef94-4435-8066-31acf23f6f99
Downward, Julian
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Ewing, Robert
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Richeldi, Luca
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Skipp, Paul
1ba7dcf6-9fe7-4b5c-a9d0-e32ed7f42aa5
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Jones, Mark
a6fd492e-058e-4e84-a486-34c6035429c1
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e

Yao, Liudi, Zhou, Yilu, Li, Juanjuan, Wickens, Leanne, Conforti, Franco, Rattu, Anna, Ibrahim, Fathima M, Alzetani, Aiman, Marshall, Benjamin, Fletcher, Sophie V., Hancock, David, Wallis, Timothy, Downward, Julian, Ewing, Robert, Richeldi, Luca, Skipp, Paul, Davies, Donna, Jones, Mark and Wang, Yihua (2021) Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis. Journal of Biological Chemistry, 297 (3). (doi:10.1016/j.jbc.2021.101096).

Record type: Article

Abstract

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.

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Accepted/In Press date: 17 August 2021
e-pub ahead of print date: 18 August 2021
Published date: 18 August 2021

Identifiers

Local EPrints ID: 450981
URI: http://eprints.soton.ac.uk/id/eprint/450981
ISSN: 0021-9258
PURE UUID: 2562cbfe-ed66-4298-bb6b-f5f8b3731fee
ORCID for Juanjuan Li: ORCID iD orcid.org/0000-0003-2164-094X
ORCID for Timothy Wallis: ORCID iD orcid.org/0000-0001-7936-9764
ORCID for Robert Ewing: ORCID iD orcid.org/0000-0001-6510-4001
ORCID for Paul Skipp: ORCID iD orcid.org/0000-0002-2995-2959
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Mark Jones: ORCID iD orcid.org/0000-0001-6308-6014
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 31 Aug 2021 16:31
Last modified: 26 Nov 2021 03:19

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Contributors

Author: Liudi Yao
Author: Yilu Zhou
Author: Juanjuan Li ORCID iD
Author: Leanne Wickens
Author: Franco Conforti
Author: Anna Rattu
Author: Fathima M Ibrahim
Author: Aiman Alzetani
Author: Sophie V. Fletcher
Author: David Hancock
Author: Timothy Wallis ORCID iD
Author: Julian Downward
Author: Robert Ewing ORCID iD
Author: Luca Richeldi
Author: Paul Skipp ORCID iD
Author: Donna Davies ORCID iD
Author: Mark Jones ORCID iD
Author: Yihua Wang ORCID iD

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