Modeling and Characterization of Intestinal Senescence Using Human Organoids: Insights Into the Epithelial to...

Area of Science:

• Gastroenterology
• Cellular Biology
• Aging Research

Background:

• Intestinal senescence contributes to systemic aging and age-related diseases.
• Limited experimental models hinder detailed study of intestinal senescence.

Purpose of the Study:

• Establish robust human small intestinal organoid models for senescence research.
• Investigate molecular mechanisms of senescence and associated dysfunction.
• Identify potential therapeutic targets for age-related intestinal decline.

Main Methods:

• Induced cellular senescence in human small intestinal organoids using butyrate and cisplatin.
• Utilized RNA-sequencing to analyze gene expression changes.
• Assessed senescence-associated features like p16INK4a expression and SA-β-Gal activity.
• Investigated nutrient transporter expression, glucose uptake, and vitamin D responsiveness.
• Examined epithelial to mesenchymal transition (EMT) and TGF-β signaling pathways.

Main Results:

• Both agents induced senescence markers, but only cisplatin activated p53 signaling.
• Organoid models showed reduced nutrient absorption, glucose uptake, and vitamin D responsiveness.
• Cisplatin-induced senescence was linked to EMT, which was reversible via TGF-β inhibition.
• TGF-β pathway inhibition ameliorated senescence-induced inflammation and nutrient dysfunction.

Conclusions:

• Novel human intestinal organoid models effectively recapitulate features of aged or damaged intestinal tissue.
• EMT is a critical pathway in cisplatin-induced intestinal senescence and dysfunction.
• Inhibiting TGF-β signaling shows promise for mitigating intestinal senescence and dysfunction.
• These models offer a platform for developing strategies against age-related intestinal dysfunction.