LGR5 controls extracellular matrix production by stem cells in the developing intestine

Area of Science:

• Gastroenterology
• Developmental Biology
• Stem Cell Biology

Background:

• Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) marks intestinal stem cells (ISCs) and is vital for Wnt/b-catenin signaling.
• Wnt signaling is critical for intestinal development, homeostasis, and stem cell function.

Purpose of the Study:

• To investigate the role of Lgr5 in intestinal stem cell (ISC) regulation and differentiation.
• To elucidate the mechanisms by which Lgr5 controls Wnt signaling and ISC fate.

Main Methods:

• Phenotype analysis of Lgr5-eGFP-IRES-Cre and Lgr5-DTReGFP knockin/knockout mouse models.
• In utero and postnatal conditional ablation of Lgr5.
• Transcriptome analysis of ISCs.
• Ex vivo organoid culture system.

Main Results:

• Lgr5 deficiency during development leads to ISC amplification and premature Paneth cell differentiation, reversible with Wnt inhibitor LGK974.
• Postnatal Lgr5 ablation alters stem cell fate towards the Paneth lineage.
• Lgr5 controls fetal ISC maturation, epithelial phenotype acquisition, and extracellular matrix production.
• Lgr5 antagonizes the R-spondin 2-Wnt pathway in ISCs within organoids.

Conclusions:

• Lgr5 acts as a feedback regulator of Wnt signaling in ISCs, influencing their maturation and fate.
• Lgr5 plays a critical role in maintaining intestinal epithelial homeostasis and stem cell function.
• Understanding Lgr5's regulatory role provides insights into sophisticated Wnt signaling control in the intestine.