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

Author

Listed:
  • Catarina P. Santos

    (Spanish National Cancer Research Centre-CNIO)

  • Eleonora Lapi

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Jaime Martínez de Villarreal

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC)

  • Laura Álvaro-Espinosa

    (Spanish National Cancer Research Centre-CNIO)

  • Asunción Fernández-Barral

    (CIBERONC
    CSIC-UAM and IdiPAZ)

  • Antonio Barbáchano

    (CIBERONC
    CSIC-UAM and IdiPAZ)

  • 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
    CSIC-UAM and IdiPAZ)

  • Francisco X. Real

    (Spanish National Cancer Research Centre-CNIO
    CIBERONC
    Universitat Pompeu Fabra)

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.

Suggested Citation

  • Catarina P. Santos & Eleonora Lapi & Jaime Martínez de Villarreal & Laura Álvaro-Espinosa & Asunción Fernández-Barral & Antonio Barbáchano & Orlando Domínguez & Ashley M. Laughney & Diego Megías & Alb, 2019. "Urothelial organoids originating from Cd49fhigh mouse stem cells display Notch-dependent differentiation capacity," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12307-1
    DOI: 10.1038/s41467-019-12307-1
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    Cited by:

    1. Sakina A. Plumber & Tiffany Tate & Hikmat Al-Ahmadie & Xiao Chen & Woonyoung Choi & Merve Basar & Chao Lu & Aaron Viny & Ekatherina Batourina & Jiaqi Li & Kristjan Gretarsson & Besmira Alija & Andrei , 2024. "Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Yeo-Jun Yoon & Donghyun Kim & Kwon Yong Tak & Seungyeon Hwang & Jisun Kim & Nam Suk Sim & Jae-Min Cho & Dojin Choi & Youngmi Ji & Junho K. Hur & Hyunki Kim & Jong-Eun Park & Jae-Yol Lim, 2022. "Salivary gland organoid culture maintains distinct glandular properties of murine and human major salivary glands," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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