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

Liudi Yao, Franco Conforti, Charlotte Hill, Joseph Bell, Leena Drawater, Juanjuan Li, Dian Liu, Hua Xiong, Aiman Alzetani, Serena J Chee, Ben G Marshall, Sophie V Fletcher, David Hancock, Mark Coldwell, Xianglin Yuan, Christian H Ottensmeier, Julian Downward, Jane E Collins, Rob M Ewing, Luca RicheldiPaul Skipp, Mark G Jones, Donna E Davies, Yihua Wang

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusE-pub ahead of print - Jul 26 2018

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    Yao, L., Conforti, F., Hill, C., Bell, J., Drawater, L., Li, J., Liu, D., Xiong, H., Alzetani, A., Chee, S. J., Marshall, B. G., Fletcher, S. V., Hancock, D., Coldwell, M., Yuan, X., Ottensmeier, C. H., Downward, J., Collins, J. E., Ewing, R. M., ... Wang, Y. (2018). Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis. Cell Death and Differentiation. https://doi.org/10.1038/s41418-018-0175-7