Sep 29, 2019

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

Nature Communications
Catarina P SantosFrancisco X Real

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 and scRNA-Seq, confirms that Notch signaling is required for differentiation. Urothelial organoids provide a powerful tool to study cell regeneration and differentiation.

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Mentioned in this Paper

Biological Markers
Peroxisome Proliferator-Activated Receptors
Sequence Determinations, RNA
Transcription, Genetic
WNT1
Gene Expression
Cell Proliferation
Ribosomes
Epidermal Growth Factor Receptor
Natural Regeneration

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