Urothelial organoids originating from Cd49fhigh mouse stem cells display Notch-dependent differentiation capacity

Catarina P. Santos, Eleonora Lapi, Jaime Martínez de Villarreal, Laura Álvaro-Espinosa, Asunción Fernández-Barral, Antonio Barbáchano, Orlando Domínguez, Ashley M. Laughney, Diego Megías, Alberto Muñoz and Francisco X. Real ()
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Catarina P. Santos: Spanish National Cancer Research Centre-CNIO
Eleonora Lapi: Spanish National Cancer Research Centre-CNIO
Jaime Martínez de Villarreal: Spanish National Cancer Research Centre-CNIO
Laura Álvaro-Espinosa: Spanish National Cancer Research Centre-CNIO
Asunción Fernández-Barral: CIBERONC
Antonio Barbáchano: CIBERONC
Orlando Domínguez: Spanish National Cancer Research Centre-CNIO
Ashley M. Laughney: Weil Cornell Medicine
Diego Megías: Spanish National Cancer Research Centre-CNIO
Alberto Muñoz: CIBERONC
Francisco X. Real: Spanish National Cancer Research Centre-CNIO

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Understanding urothelial stem cell biology and differentiation has been limited by the lack of methods for their unlimited propagation. Here, we establish mouse urothelial organoids that can be maintained uninterruptedly for >1 year. Organoid growth is dependent on EGF and Wnt activators. High CD49f/ITGA6 expression features a subpopulation of organoid-forming cells expressing basal markers. Upon differentiation, multilayered organoids undergo reduced proliferation, decreased cell layer number, urothelial program activation, and acquisition of barrier function. Pharmacological modulation of PPARγ and EGFR promotes differentiation. RNA sequencing highlighted genesets enriched in proliferative organoids (i.e. ribosome) and transcriptional networks involved in differentiation, including expression of Wnt ligands and Notch components. Single-cell RNA sequencing (scRNA-Seq) analysis of the organoids revealed five clusters with distinct gene expression profiles. Together with the use of γ-secretase inhibitors, scRNA-Seq confirms that Notch signaling is required for differentiation. Urothelial organoids provide a powerful tool to study cell regeneration and differentiation.

Date: 2019
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DOI: 10.1038/s41467-019-12307-1

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