HES1 deficiency impairs development of human intestinal mesenchyme by suppressing WNT5A expression

Area of Science:

• Gastroenterology
• Developmental Biology
• Cancer Research

Background:

• Serious intestinal side-effects of cancer therapies targeting the NOTCH-HES1 pathway necessitate understanding its role at the human organ level.
• The NOTCH-HES1 pathway is implicated in human cancer differentiation therapy, highlighting the need for organ-level insights.

Purpose of the Study:

• To investigate the role of HES1 in human intestinal organoid (HIO) development and function.
• To elucidate the molecular mechanisms underlying HES1 signaling in intestinal epithelial and stromal development.

Main Methods:

• Endogenous HES1 knockout in human embryonic stem cells (hESCs) followed by differentiation into HIOs.
• RNA-sequencing (RNA-Seq) to analyze gene expression changes in HES1-deficient HIOs.
• In vitro studies using intestinal fibroblast cell lines to assess HES1 and WNT5A interactions.

Main Results:

• HES1 deficiency in HIOs led to impaired mesenchymal cell development and increased secretory epithelium differentiation.
• RNA-Seq data suggested WNT5A signaling downregulation contributes to the inhibited mesenchymal development.
• HES1 was found to activate WNT5A-induced fibroblast growth and migration, indicating its role in epithelial-mesenchymal crosstalk.

Conclusions:

• HES1 plays distinct roles in both stromal and epithelial development within the human intestinal mucosa.
• The findings identify specific molecular mechanisms of HES1 signaling, crucial for understanding its involvement in intestinal development and cancer therapy.
• This study provides a foundation for targeted therapeutic strategies addressing NOTCH-HES1 pathway-related side effects in cancer treatment.