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Urothelial organoids originate from Cd49f-High stem cells and display Notch-dependent differentiation capacity

View ORCID ProfileFrancisco X Real, Catarina P Santos, Eleonora Lapi, Laura Alvaro-Espinosa, Asuncion Fernandez-Barral, Antonio Barbachano, Diego Megias, Alberto Munoz
doi: https://doi.org/10.1101/287979
Francisco X Real
Spanish National Cancer Research Center - CNIO;
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Catarina P Santos
Spanish National Cancer Research Center - CNIO;
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Eleonora Lapi
Spanish National Cancer Research Center - CNIO;
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Laura Alvaro-Espinosa
Spanish National Cancer Research Center - CNIO;
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Asuncion Fernandez-Barral
Instituto de Investigaciones Biomedicas-CSIC
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Antonio Barbachano
Instituto de Investigaciones Biomedicas-CSIC
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Diego Megias
Spanish National Cancer Research Center - CNIO;
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Alberto Munoz
Instituto de Investigaciones Biomedicas-CSIC
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Abstract

The urothelium is a specialized stratified epithelium with unique structural and functional features. Understanding the mechanisms involved in urothelial stem cell biology and differentiation has been limited by the lack of methods for unlimited propagation. Here, we establish normal mouse urothelial organoid (NMU-o) cultures 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 urothelial stem cells expressing basal markers. On induction of differentiation, multilayered organoids show reduced layer number, acquire barrier function, and activate the urothelial program, including expression of uroplakins and tight junction components. Combined pharmacological modulation of PPAR gamma and EGFR was most potent driving cell differentiation. Transcriptome analysis of organoids widely validates the system, highlights the transcriptional networks involved, and reveals NOTCH signaling as a novel pathway required for normal urothelial organoid differentiation.

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  • Posted March 23, 2018.

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Urothelial organoids originate from Cd49f-High stem cells and display Notch-dependent differentiation capacity
Francisco X Real, Catarina P Santos, Eleonora Lapi, Laura Alvaro-Espinosa, Asuncion Fernandez-Barral, Antonio Barbachano, Diego Megias, Alberto Munoz
bioRxiv 287979; doi: https://doi.org/10.1101/287979
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Urothelial organoids originate from Cd49f-High stem cells and display Notch-dependent differentiation capacity
Francisco X Real, Catarina P Santos, Eleonora Lapi, Laura Alvaro-Espinosa, Asuncion Fernandez-Barral, Antonio Barbachano, Diego Megias, Alberto Munoz
bioRxiv 287979; doi: https://doi.org/10.1101/287979

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