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dc.contributor.author | Santos, Catarina P | |
dc.contributor.author | Lapi, Eleonora | |
dc.contributor.author | Martínez de Villarreal, Jaime | |
dc.contributor.author | Álvaro-Espinosa, Laura | |
dc.contributor.author | Fernández-Barral, Asunción | |
dc.contributor.author | Barbáchano, Antonio | |
dc.contributor.author | Dominguez, Orlando | |
dc.contributor.author | Laughney, Ashley M | |
dc.contributor.author | Megias Vazquez, Diego | |
dc.contributor.author | Muñoz, Alberto | |
dc.contributor.author | Real Arribas, Francisco | |
dc.date.accessioned | 2020-03-24T19:12:44Z | |
dc.date.available | 2020-03-24T19:12:44Z | |
dc.date.issued | 2019-09-27 | |
dc.identifier.citation | Nat Commun. 2019;10(1):4407. | es_ES |
dc.identifier.issn | 2041-1723 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/9319 | |
dc.description.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. | es_ES |
dc.description.sponsorship | We thank the members of the Epithelial Carcinogenesis Group and the CNIO Bioinformatics Unit for valuable discussions; N. del Pozo, Y. Gonzalo, and R. Serrano for help with animal experimentation; E. Carrillo-de-Santa-Pau and O. Grana for help with bioinformatics analyses; E. Osinaga for help with lectin assays; A. Garcia-Espana for providing antibodies; A. Bigas, D. Chondronasiou, G. Mata Martinez, M. Deblas, J. Gomez-Alonso, J. Gonzalez, A. Klinakis, S. Lowe, N. Malats, L. Martinez, J.L. MartinezTorrecuadrada, M. Perez Martinez, M. Ricote, M. Blasco, and M. Serrano for other valuable contributions; and J. Paramio, P. Martinelli, and M. Marques for comments to the manuscript. We thank E. Batlle and his group for many valuable suggestions. This work was supported, in part, by grants from Spanish Ministry of Economy, Industry and Competitiveness (SAF2016-76377-R), CIBERONC (CB16/12/00453 and CB16/12/00273), and Fundacion Cientifica de la Asociacion Espanola Contra el Cancer. CNIO is supported by Ministerio de Ciencia, Innovacion y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Cell Differentiation | es_ES |
dc.subject.mesh | Cell Line, Tumor | es_ES |
dc.subject.mesh | Epidermal Growth Factor | es_ES |
dc.subject.mesh | Gene Expression Profiling | es_ES |
dc.subject.mesh | Gene Ontology | es_ES |
dc.subject.mesh | Gene Regulatory Networks | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Integrin alpha6 | es_ES |
dc.subject.mesh | Mice, 129 Strain | es_ES |
dc.subject.mesh | Mice, Inbred C57BL | es_ES |
dc.subject.mesh | Mice, Nude | es_ES |
dc.subject.mesh | Mice, Transgenic | es_ES |
dc.subject.mesh | Organoids | es_ES |
dc.subject.mesh | Receptors, Notch | es_ES |
dc.subject.mesh | Single-Cell Analysis | es_ES |
dc.subject.mesh | Stem Cells | es_ES |
dc.subject.mesh | Urothelium | es_ES |
dc.title | Urothelial organoids originating from Cd49fhigh mouse stem cells display Notch-dependent differentiation capacity | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 31562298 | es_ES |
dc.format.volume | 10 | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 4407 | es_ES |
dc.identifier.doi | 10.1038/s41467-019-12307-1 | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Centro de Investigación Biomédica en Red - CIBERONC (Cáncer) | |
dc.contributor.funder | Asociación Española Contra el Cáncer | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2041-1723 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/s41467-019-12307-1. | es_ES |
dc.identifier.journal | Nature communications | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Carcinogénesis Epitelial | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SAF2016-76377-R | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/CB16/12/00453 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/CB16/12/00273 | es_ES |
dc.relation.projectID | info:eu_repo/grantAgreement/ES/SEV-2015-0510 | es_ES |
dc.rights.accessRights | open access | es_ES |