Sex-Dependent Effects of Epithelial M3R Knockout on Colonic Progenitor Cells

Overview

This study demonstrates that epithelial muscarinic receptor 3 (M3R) ablation in mice leads to sex-specific alterations in colonic progenitor cell populations and differential responses to intestinal injury. Male mice exhibited a reduction in Lgr5+ progenitor cells and severe colitis upon M3R knockout, whereas females showed an expansion of these cells and were protected from inflammation.

Background

Muscarinic acetylcholine receptors (mAChRs), particularly the M3 subtype, are expressed in intestinal epithelial cells and regulate intestinal homeostasis and regeneration. Previous studies have shown that M3R signaling influences epithelial differentiation and barrier integrity, but sex-specific effects remain unclear. Sexual dimorphism in intestinal stem cell function and disease susceptibility suggests that cholinergic signaling may differentially modulate intestinal epithelial cells in males and females.

Data Highlights

Key Findings

• Epithelial M3R knockout causes a marked decrease in Lgr5-expressing progenitor cells in male colonic tissue.
• Female mice with M3R ablation show an expansion of Lgr5+ progenitor cells, indicating sex-dependent regulation.
• Young female mice with reduced circulating sex hormones lose the progenitor cell expansion, implicating hormonal influence.
• Male M3R knockout mice develop severe inflammation after experimental colitis induction, whereas females are largely protected.
• Muscarinic receptor agonism modulates epithelial cell homeostasis in a sex-specific manner in both murine and human colonoids.

Clinical Implications

These findings highlight the importance of considering patient sex when targeting muscarinic receptor signaling pathways for intestinal inflammatory diseases. Therapeutic strategies modulating cholinergic signaling may need to be tailored to sex-specific responses to optimize efficacy and minimize adverse effects. Additionally, hormonal status could influence treatment outcomes in colonic injury and regeneration.

Conclusion

Epithelial M3R signaling exerts sex-dependent effects on colonic progenitor cell dynamics and injury responses, underscoring the need to incorporate sex as a biological variable in developing cholinergic-based therapies for colonic inflammation.

References

1. Original Article 2024 -- Sex-Dependent Effects of Epithelial Muscarinic Receptor 3 Knockout on Colonic Progenitor Cell Dynamics and Intestinal Injury Response