The Roles of EGFR and FGFR2 in Cell Shape Maintenance of Human Lung Tip Progenitor Epithelial Cells

The Roles of EGFR and FGFR2 in Cell Shape Maintenance of Human Lung Tip Progenitor Epithelial Cells Recent work in the developing human lung has identified distal tip epithelial progenitors that are SOX9+SOX2+ and give rise to all lung epithelial cell types (Danopoulos et al., 2019b; Miller et al., 2018; Nikolic et al., 2017). Human epithelial progenitor cells derived from the pseudoglandular stage (~5 to 17 post conception weeks, pcw) have been cultured as self-renewing organoids in a chemically-defined medium (Miller et al., 2018; Nikolic et al., 2017). In this condition, the progenitor cells retain their columnar cell shape, resembling the morphology of the developing lung tip epithelia in vivo. Cell shape and cell fate are highly coordinated during development. Therefore, I used the organoid system to identify signalling pathways that maintain the shape of human lung tip progenitor cells. I have found that EGF, FGF7 and FGF10 have distinct functions in the regulation of lung tip progenitor cell shape. FGF7 promotes columnar cell shape in primary tip progenitor cells, whereas EGF and FGF10 cannot. FGF7 activates sustained MAPK/ERK and PI3K/AKT pathways when assayed using kinase translocation reporters, and inhibition experiments show that both downstream pathways are required for cell shape maintenance. The MAPK/ERK and PI3K/AKT pathways regulate proliferation, promote columnar cell shape and maintain junction organisation. I show that integrin signalling is a key pathway downstream of MAPK/ERK in the tip progenitor cells; disrupting integrin alters cell polarity, cell adhesion and tight junction assembly. These results will facilitate organoid-based studies of human lung development and regeneration. My work provides a convenient platform for dissecting RTK ligand function in epithelial cells and will facilitate future studies of cell shape and cell fate coordination in organoid-based research.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Liu, Shuyu

Advisor dc:contributor.advisor

• Rawlins, Emma

• Cell shape
• Lung development
• Organoid
• RTK signalling

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.95207

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/347790