EPFL scientists have shown that a gene linked to a rare childhood disease is essential for regenerating intestinal stem cells after injury.
Our intestines are constantly renewing themselves, replacing cells every few days to maintain a healthy gut lining. But when injury strikes, the body needs to reboot this system fast. In rare cases, the system fails entirely, leading to severe illness and even death.
One such case is Hyaline Fibromatosis Syndrome (HFS), a rare genetic disorder that can cause painful skin lumps, joint problems, and in its most severe form, lethal diarrhea in infants. This extreme intestinal symptom has long puzzled doctors, as the intestines in HFS patients can appear normal under the microscope. The disease is known to be caused by mutations in a gene called CMG2, but its role in gut biology remained unclear.
Intestinal repair relies on a small group of stem cells that live at the base of intestinal crypts. These cells can regenerate the gut lining after injury, and when they're lost, other nearby cells can revert to a primitive, fetal-like state to restore the stem cell pool. This process is tightly controlled by molecular signals, including a well-known pathway called Wnt signaling. If any part of this regeneration chain fails, healing stalls.
A team led by Professor Gisou van der Goot, head of the Laboratory of Cell and Membrane Biology at EPFL, have now uncovered a hidden role for CMG2 in this healing process. Using a mouse model of HFS, they found that while the gut appears normal under everyday conditions, it fails to regenerate after injury. The results, published in EMBO Molecular Medicine, help explain the life-threatening intestinal problems seen in severe HFS cases and reveal new insights into how our bodies repair damaged tissue.
The researchers used mice lacking CMG2 and exposed them to a chemical that mimicks gut injury by inducing colitis. This caused both normal and mutant mice to develop similar levels of inflammation and tissue damage. But when the chemical was removed, only the normal mice recovered. The CMG2-deficient mice continued to deteriorate, losing weight and showing persistent signs of inflammation.
To understand why, the researchers looked at the process of stem cell regeneration. Normally, cells first shift into a fetal-like state, then transition back into adult stem cells marked by the gene Lgr5; the transition depends on activation of Wnt signaling. In the mutant mice, the initial switch to fetal-like cells occurred normally, but they failed to turn back into to adult stem cells.
The team traced this failure to a breakdown in Wnt signaling, specifically a failure of β-catenin to enter the cell nucleus and activate genes needed for stem cell identity.
The study shows that CMG2 is not required for normal gut maintenance, but becomes essential when the tissue is damaged. Without it, the critical Wnt signal fails to kick in during regeneration, blocking the restoration of the stem cell pool. This also could explain why HFS patients with severe CMG2 mutations suffer from life-threatening diarrhea following intestinal stress.
The study sheds light on a rare genetic disorder, but also on how the gut repairs itself. Its findings suggest that CMG2 acts as a context-specific amplifier of Wnt signaling during injury. This could have wider relevance for regenerative medicine and diseases like inflammatory bowel disease, where stem cell replenishment is critical.
Other contributors
- EPFL BioImaging and Optics Core Facility
- Nexco Analytics
