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Paracrine signalling during ZEB1-mediated epithelial mesenchymal transition augments local myofibroblast differentiation in lung fibrosis

Paracrine signalling during ZEB1-mediated epithelial mesenchymal transition augments local myofibroblast differentiation in lung fibrosis
Paracrine signalling during ZEB1-mediated epithelial mesenchymal transition augments local myofibroblast differentiation in lung fibrosis
The contribution of epithelial-mesenchymal transition (EMT) to human lung fibrogenesis is controversial. Here we provide evidence that ZEB1-mediated EMT in human alveolar epithelial type II (ATII) cells contributes to development of lung fibrosis by paracrine signalling to underlying fibroblasts. Activation of EGFR-RAS-ERK signalling in ATII cells induced EMT via ZEB1. ATII cells had extremely low extracellular matrix gene expression even after induction of EMT, however conditioned media from ATII cells undergoing RAS-induced EMT augmented TGFβ-induced profibrogenic responses in lung fibroblasts. This epithelial-mesenchymal crosstalk was controlled by ZEB1 via the expression of tissue plasminogen activator (tPA). In human fibrotic lung tissue, nuclear ZEB1 expression was detected in alveolar epithelium adjacent to sites of extracellular matrix (ECM) deposition, suggesting that ZEB1-mediated paracrine signalling has the potential to contribute to early fibrotic changes in the lung interstitium. Targeting this novel ZEB1 regulatory axis may be a viable strategy for the treatment of pulmonary fibrosis.
1350-9047
943-957
Yao, Liudi
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Conforti, Franco
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Hill, Charlotte
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Bell, Joseph
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Drawater, Leena
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Li, Juanjuan
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Liu, Dian
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Xiong, Hua
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Alzetani, Aiman
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Chee, Serena J.
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Marshall, Ben G.
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Fletcher, Sophie
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Hancock, David
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Coldwell, Mark
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Yuan, Xianglin
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Ottensmeier, Christian
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Downward, Julian
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Collins, Jane
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Ewing, Robert
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Richeldi, Luca
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Skipp, Paul
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Jones, Mark
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Davies, Donna
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Wang, Yihua
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Yao, Liudi
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Conforti, Franco
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Hill, Charlotte
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Bell, Joseph
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Drawater, Leena
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Li, Juanjuan
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Liu, Dian
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Xiong, Hua
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Alzetani, Aiman
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Chee, Serena J.
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Marshall, Ben G.
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Fletcher, Sophie
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Hancock, David
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Coldwell, Mark
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Yuan, Xianglin
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Ottensmeier, Christian
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Downward, Julian
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Collins, Jane
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Ewing, Robert
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Richeldi, Luca
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Skipp, Paul
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Jones, Mark
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Davies, Donna
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Wang, Yihua
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Yao, Liudi, Conforti, Franco, Hill, Charlotte, Bell, Joseph, Drawater, Leena, Li, Juanjuan, Liu, Dian, Xiong, Hua, Alzetani, Aiman, Chee, Serena J., Marshall, Ben G., Fletcher, Sophie, Hancock, David, Coldwell, Mark, Yuan, Xianglin, Ottensmeier, Christian, Downward, Julian, Collins, Jane, Ewing, Robert, Richeldi, Luca, Skipp, Paul, Jones, Mark, Davies, Donna and Wang, Yihua (2019) Paracrine signalling during ZEB1-mediated epithelial mesenchymal transition augments local myofibroblast differentiation in lung fibrosis. Cell Death and Differentiation, 26 (5), 943-957. (doi:10.1038/s41418-018-0175-7).

Record type: Article

Abstract

The contribution of epithelial-mesenchymal transition (EMT) to human lung fibrogenesis is controversial. Here we provide evidence that ZEB1-mediated EMT in human alveolar epithelial type II (ATII) cells contributes to development of lung fibrosis by paracrine signalling to underlying fibroblasts. Activation of EGFR-RAS-ERK signalling in ATII cells induced EMT via ZEB1. ATII cells had extremely low extracellular matrix gene expression even after induction of EMT, however conditioned media from ATII cells undergoing RAS-induced EMT augmented TGFβ-induced profibrogenic responses in lung fibroblasts. This epithelial-mesenchymal crosstalk was controlled by ZEB1 via the expression of tissue plasminogen activator (tPA). In human fibrotic lung tissue, nuclear ZEB1 expression was detected in alveolar epithelium adjacent to sites of extracellular matrix (ECM) deposition, suggesting that ZEB1-mediated paracrine signalling has the potential to contribute to early fibrotic changes in the lung interstitium. Targeting this novel ZEB1 regulatory axis may be a viable strategy for the treatment of pulmonary fibrosis.

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More information

Accepted/In Press date: 9 July 2018
e-pub ahead of print date: 26 July 2018
Published date: May 2019

Identifiers

Local EPrints ID: 422294
URI: https://eprints.soton.ac.uk/id/eprint/422294
ISSN: 1350-9047
PURE UUID: f4c39644-2d89-4330-bc06-963365ffb762
ORCID for Mark Coldwell: ORCID iD orcid.org/0000-0002-6243-3886
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 Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 20 Jul 2018 16:30
Last modified: 10 Dec 2019 05:18

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Contributors

Author: Liudi Yao
Author: Franco Conforti
Author: Charlotte Hill
Author: Joseph Bell
Author: Leena Drawater
Author: Juanjuan Li
Author: Dian Liu
Author: Hua Xiong
Author: Aiman Alzetani
Author: Serena J. Chee
Author: Ben G. Marshall
Author: Sophie Fletcher
Author: David Hancock
Author: Mark Coldwell ORCID iD
Author: Xianglin Yuan
Author: Julian Downward
Author: Jane Collins
Author: Robert Ewing ORCID iD
Author: Luca Richeldi
Author: Paul Skipp ORCID iD
Author: Mark Jones
Author: Donna Davies ORCID iD
Author: Yihua Wang ORCID iD

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