TNFα Induces LGR5+ Stem Cell Dysfunction In Patients With Crohn's Disease

Area of Science:

• Gastroenterology
• Cell Biology
• Immunology

Background:

• Tumor necrosis factor alpha (TNFα) is a key driver of tissue damage in Crohn's disease (CD) pathogenesis.
• Patient-derived intestinal organoids (enteroids) serve as a model to study CD-specific intestinal epithelial characteristics.

Purpose of the Study:

• To investigate intestinal epithelial responses to TNFα in enteroids from healthy controls and CD patients.
• To compare the effects of TNFα on stem cell populations in control versus CD-derived enteroids.

Main Methods:

• Human enteroids from CD patients and controls were treated with TNFα.
• Cell viability and gene expression patterns were analyzed using immunohistochemistry and RNA sequencing.
• Single-cell RNA sequencing was employed to characterize stem cell subpopulations.

Main Results:

• TNFα induced MLKL-mediated necroptosis, more pronounced in CD enteroids.
• TNFα treatment expanded intestinal stem cell (ISC) populations, with distinct subpopulations in control (LGR5+) and CD (BMI1+) enteroids.
• Prostaglandin E2 (PGE2) restored LGR5+ ISC function, improving organoid viability and wound healing in TNFα-treated CD enteroids.

Conclusions:

• TNFα increases necroptosis and expands LGR5+ ISCs, but causes LGR5+ stem cell dysfunction in CD.
• Exogenous PGE2 can restore LGR5+ stem cell function in CD patient-derived enteroids.
• PGE2 holds potential for promoting mucosal healing in Crohn's disease patients.