A urine-dependent human urothelial organoid offers a potential alternative to rodent models of infection
Authors
Harry Horsley, Dhanuson Dharmasena, James Malone-Lee & Jennifer L. Rohn
Institution
Chronic UTI Group, Centre for Nephrology, University College London, London, UK
Country
United Kingdom
Year
2017
Journal
Nature - Scientific Reports
Abstract
Murine models describe a defined host/pathogen interaction for urinary tract infection, but human cell
studies are scant. Although recent human urothelial organoid models are promising, none demonstrate
long-term tolerance to urine, the natural substrate of the tissue and of the uropathogens that live
there. We developed a novel human organoid from progenitor cells which demonstrates key structural
hallmarks and biomarkers of the urothelium. After three weeks of transwell culture with 100% urine
at the apical interface, the organoid stratified into multiple layers. The apical surface differentiated
into enlarged and flattened umbrella-like cells bearing characteristic tight junctions, structures
resembling asymmetric unit membrane plaques, and a glycosaminoglycan layer. The apical cells also
expressed cytokeratin-20, a spatial feature of the mammalian urothelium. Urine itself was necessary
for full development, and undifferentiated cells were urine-tolerant despite the lack of membrane
plaques and a glycosaminoglycan layer. Infection with Enterococcus faecalis revealed the expected
invasive outcome, including urothelial sloughing and the formation of intracellular colonies similar to
those previously observed in patient cells. This new biomimetic model could help illuminate invasive
behaviours of uropathogens, and serve as a reproducible test bed for disease formation, treatment and
resolution in patients.