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RTK signalling promotes epithelial columnar cell shape and apical junction maintenance in human lung progenitor cells.

Published version

Published version
Peer-reviewed

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Authors

Liu, Shuyu 
Sun, Dawei 
Butler, Richard 

Abstract

Multipotent epithelial progenitor cells can be expanded from human embryonic lungs as organoids. and maintained in a self-renewing state using a defined medium. The organoid cells are columnar, resembling the cell morphology of the developing lung tip epithelium in vivo. Cell shape dynamics and fate are tightly coordinated during development. We therefore used the organoid system to identify signalling pathways that maintain the columnar shape of human lung tip progenitors. We found that EGF, FGF7 and FGF10 have distinct functions in lung tip progenitors. FGF7 activates MAPK/ERK and PI3K/AKT signalling and is sufficient to promote columnar cell shape in primary tip progenitors. Inhibitor experiments show that MAPK/ERK and PI3K/AKT signalling are key downstream pathways, regulating cell proliferation, columnar cell shape and cell junctions. We identified integrin signalling as a key pathway downstream of MAPK/ERK in the tip progenitors; disrupting integrin alters polarity, cell adhesion and tight junction assembly. By contrast, stimulation with FGF10 or EGF alone is not sufficient to maintain organoid columnar cell shape. This study employs organoids to provide insight into the cellular mechanisms regulating human lung development.

Description

Peer reviewed: True


Acknowledgements: We acknowledge the Gurdon Institute Imaging Facility and Dr Karin Mueller of Cambridge Advanced Imaging Centre for microscopy support. Core funding to the Gurdon Institute comes from the Wellcome Trust (203144/Z/16/Z) and Cancer Research UK (C6946/A24843).


Funder: University of Cambridge; doi: http://dx.doi.org/10.13039/501100000735

Keywords

EGF, FGF, Integrin, KTR reporter, Organoid

Journal Title

Development

Conference Name

Journal ISSN

0950-1991
1477-9129

Volume Title

Publisher

The Company of Biologists
Sponsorship
Medical Research Council (MR/P009581/1)
Wellcome Trust (109146/Z/15/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust, CRUK, UKRI MRC