Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids

Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25-dihydroxyvitamin D3 (calcitriol), the active...

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Detalhes bibliográficos
Autores: Fernández-Barral, Asunción, Costales-Carrera, Alba, Buira, Sandra P., Jung, Peter, Ferrer-Mayorga, Gemma, Larriba, María Jesús, Bustamante-Madrid, Pilar, Domínguez, Orlando, Real, Francisco X., Guerra-Pastrián, Laura, Lafarga, Miguel, García-Olmo, Damián, Cantero, Ramón, Peso, Luis del, Batlle, Eduard, Rojo, Federico, Muñoz Terol, Alberto, Barbáchano, Antonio
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/186482
Acesso em linha:http://hdl.handle.net/10261/186482
Access Level:acceso abierto
Palavra-chave:Colon cancer
Colon stem cells
Organoids
Stemness genes
Vitamin D
Descrição
Resumo:Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25-dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids calcitriol upregulates stemness-related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7 and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness-related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.

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