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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Bibliographic Details
Authors: 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, Del Peso, Luis, Batlle Gómez, Eduard, Rojo, Federico, Muñoz, Alberto, Barbáchano, Antonio
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/42377
Online Access:http://hdl.handle.net/10230/42377
http://dx.doi.org/10.1111/febs.14998
Access Level:Open access
Keyword:Colon cancer
Colon stem cells
Organoids
Stemness genes
Vitamin D
Description
Summary: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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