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HES1 deficiency impairs development of human intestinal mesenchyme by suppressing WNT5A expression
Ist Teil von
Biochemical and biophysical research communications, 2023-05, Vol.655, p.50-58
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2023
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Serious intestinal side-effects that target the NOTCH-HES1 pathway in human cancer differentiation therapy make it necessary to understand the pathway at the human organ level. Herein, we endogenously introduced HES1−/− mutations into human embryonic stem cells (hESCs) and differentiated them into human intestinal organoids (HIO). The HES1−/− hESCs retained ES cell properties and showed gene expression patterns similar to those of wild-type hESCs when they differentiated into definitive endoderm and hindgut. During the formation of the HES1−/− lumen we noted an impaired development of mesenchymal cells in addition to the increased differentiation of secretory epithelium. RNA-Seq revealed that inhibited development of the mesenchymal cells may have been due to a downregulation of WNT5A signaling. Overexpression of HES1 and silencing of WNT5A in the intestinal fibroblast cell line CCD-18Co indicated that HES1 was involved in the activation of WNT5A-induced fibroblast growth and migration, suggesting the likelihood of the Notch pathway in epithelial-mesenchymal crosstalk. Our results facilitated the identification of more precise underlying molecular mechanisms displaying distinct roles in HES1 signaling in stromal and epithelial development in human intestinal mucosa.
•HES1 is critical to lumen differentiation and maturation of human intestinal organoid development.•Solely disrupting HES1 was sufficient to promote the fate of secretory cells in human intestinal epithelium.•HES1 involved in subepithelial mesenchymal development by affecting WNT5A expression.