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

Abstract: 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 1?,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.

 Fuente: FEBS J, 287 (1), 53-72 Jan 2020

 Editorial: Wiley

 Año de publicación: 2020

 Nº de páginas: 20

 Tipo de publicación: Artículo de Revista

 DOI: 10.1111/febs.14998

 ISSN: 1742-464X,1742-4658

 Proyecto español: SAF2016-76377-R

 Url de la publicación: https://www.doi.org/10.1111/febs.14998

Autoría

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

GARCÍA-OLMO, DAMIÁN

CANTERO, RAMÓN

PESO, LUIS DEL

BATLLE, EDUARD

ROJO, FEDERICO

MUÑOZ, ALBERTO

BARBÁCHANO, ANTONIO