Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis.
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Date
2019-05ICR Author
Author
Yao, L
Conforti, F
Hill, C
Bell, J
Drawater, L
Li, J
Liu, D
Xiong, H
Alzetani, A
Chee, SJ
Marshall, BG
Fletcher, SV
Hancock, D
Coldwell, M
Yuan, X
Ottensmeier, CH
Downward, J
Collins, JE
Ewing, RM
Richeldi, L
Skipp, P
Jones, MG
Davies, DE
Wang, Y
Type
Journal Article
Metadata
Show full item recordAbstract
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 the 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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Subject
Lung
Cell Line
Extracellular Matrix
Epithelial Cells
Humans
Respiratory Tract Diseases
Fibrosis
Paracrine Communication
Cell Differentiation
Gene Expression Regulation
Myofibroblasts
Epithelial-Mesenchymal Transition
Zinc Finger E-box-Binding Homeobox 1
Research team
Lung Cancer Group
Language
eng
Date accepted
2018-07-09
License start date
2019-05
Citation
Cell death and differentiation, 2019, 26 (5), pp. 943 - 957