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Impaired Bmp signaling in Foxl1+ telocyte influence the maintenance of the intestinal stem cell niche
Author(s) -
Perreault Nathalie,
Servant Raphaelle,
Pomerleau Veronique,
Jones Christine,
Boudreau Francois
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05979
Subject(s) - microbiology and biotechnology , crypt , biology , stem cell , intestinal epithelium , cdx2 , epithelium , endocrinology , homeobox , transcription factor , genetics , gene
New components of the intestinal stem cell niche are constantly being discovered. Recently, the subepithelial Foxl1 + telocytes (TC Foxl1+ ) were found to play a key role in maintaining and regulating intestinal crypt homeostasis. TC Foxl1+ produce crucial niche components such as WNT2b, WNT5a and RSPO3 as well as the Bone Morphogenic Proteins (BMP) inhibitors Gremlin 1 and 2. Previous work in our laboratory showed that epithelial BMP signaling is involved in terminal differentiation and maturation of cells from the secretory lineage. Our recent work showed that the loss of mesenchymal BMP signaling leads to the development of a pathological microenvironment inducing colonic and gastric polyposis in older mice, drawing attention to the impact of a pathogenic microenvironment in polyposis. By genetic means, we propose to address how BMP signaling in TC Foxl1+ modulates the intestinal stem cell niche. Using the Cre/loxP system, we generated mice with a deletion of BmpR1a in all gastrointestinal subepithelial TC Foxl1+ . Histological analysis and terminal differentiation assessment were performed with cellular staining and immunofluorescence (H&E, Alcian Blue and Lysozyme). Niche components were analysed by RT‐qPCR from crypt epithelium or total ileal RNA extracts. H&E staining on 9 months‐old BmpR1a ΔFoxl1+ and control mice ileum demonstrated perturbed architecture in the BmpR1a ΔFoxl1+ such as fused and enlarged villi compared to control mice. Alcian Blue staining showed an increase of goblet cells in the mutant mice. Electron microscopy showed that Paneth cells from mutant mice have larger vesicles than controls. The RT‐qPCR analysis showed a decrease in WNT signaling targets in the crypts epithelium cells. Indeed, LGR5 is decreased by 50% and mTERT by 34% in the mutant mice, whereas the stem cell marker BMI1 is not modulated. Maturity of Paneth cells is impaired in the mutant mice as shown by a 41% decrease in SOX9 expression. This lack in Paneth cell maturity is also reflected by a 60% decrease in WNT3 expression in BmpR1a ΔFoxl1+ mice, an important stem cell niche factor. Secretory cell determination transcription factor ATOH1 is decreased by 35% in the mutant mice. Analysis from total ileal extract revealed a decrease of WNT2b, a key niche factor from the mesenchymal cells. Thus, our results show that altering Bmp signaling in subepithelial TC Foxl1+ modulates crucial niche factors influencing intestinal stem cells homeostasis and their subsequent determination. Support or Funding Information Canadian Institutes of Health Research‐Institute of Nutrition, Metabolism and Diabetes