Genetic Discovery Unveils Key Role in Intestinal Stem Cell Regeneration for Rare Disorder

Researchers at EPFL have identified a critical function for a gene linked to a rare childhood disorder, Hyaline Fibromatosis Syndrome (HFS), in the regeneration of intestinal stem cells following injury. This groundbreaking study sheds light on the genetic mechanisms underlying gut repair processes and offers new insights into life-threatening intestinal diseases.

Our intestines are in a constant state of renewal; every few days, the lining must regenerate to maintain healthy gut function. When injury occurs, the body relies on a specialized group of stem cells located at the base of intestinal crypts to rebuild the tissue. In some rare conditions like HFS, this regenerative process is severely impaired, leading to severe complications such as lethal diarrhea. HFS is caused by mutations in the CMG2 gene, known to influence tissue development, yet its exact role in gut healing was previously unclear.

The study focused on understanding how intestinal regeneration occurs, particularly how stem cells are activated after injury. The process involves stem cells transitioning through a fetal-like state before returning to their mature form, which is regulated by molecular signals like the Wnt pathway. Disruption in this pathway can halt healing.

Led by Professor Gisou van der Goot at EPFL, the research team employed mouse models deficient in CMG2. They observed that under normal conditions, these mice exhibited healthy intestines. However, when subjected to a chemical model simulating gut injury, the CMG2-lacking mice failed to regenerate effectively. While initial fetal-like cell activation was normal, these cells could not revert to healthy adult stem cells due to impaired Wnt signaling, specifically a failure of β-catenin to activate genes in the nucleus essential for stem cell identity.

These findings illustrate that CMG2 is not necessary for everyday gut maintenance but becomes essential under stress or injury conditions. Without functional CMG2, the Wnt signaling pathway falters during regeneration, preventing stem cells from restoring the intestinal lining. This failure could explain the severe diarrhea in HFS patients following intestinal stress and highlights the importance of CMG2 in tissue repair.

Published in EMBO Molecular Medicine, this research advances our understanding of genetic disorders affecting tissue regeneration. It also emphasizes the potential of targeting Wnt pathway modulation in regenerative therapies and diseases such as inflammatory bowel disease. Overall, the study reveals that CMG2 acts as a context-dependent enhancer of Wnt signaling, crucial for effective gut healing after injury.

Source: https://medicalxpress.com/news/2025-09-gene-rare-disorder-crucial-intestinal.html