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Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids
Author(s) -
FernándezBarral Asunción,
CostalesCarrera Alba,
Buira Sandra P.,
Jung Peter,
FerrerMayorga Gemma,
Larriba María Jesús,
BustamanteMadrid Pilar,
Domínguez Orlando,
Real Francisco X.,
GuerraPastrián Laura,
Lafarga Miguel,
GarcíaOlmo Damián,
Cantero Ramón,
Peso Luis,
Batlle Eduard,
Rojo Federico,
Muñoz Alberto,
Barbáchano Antonio
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14998
Subject(s) - organoid , stem cell , vitamin , microbiology and biotechnology , vitamin d and neurology , biology , cancer research , chemistry , endocrinology
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 D 3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNA scope in situ hybridization that vitamin D receptor ( VDR ) is unexpectedly expressed in LGR 5 + 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 LGR 5 , SMOC 2 , LRIG 1 , MSI 1 , PTK 7 , and MEX 3A , 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 .