A Key Enzyme Regulates Cell Fate During Intestinal Regeneration

Researchers at Memorial Sloan Kettering Cancer Center have uncovered a crucial metabolic switch that influences whether intestinal stem cells develop into absorptive or secretory cells. The enzyme OGDH plays a pivotal role in this process: its activity can either promote cell proliferation or redirect cell lineage toward secretory functions, which include mucus secretion and antimicrobial production essential for gut health. Manipulating OGDH impacts tissue regeneration and recovery, particularly in conditions like colitis.

In the intestinal lining, stem cells maintain a fine balance between self-renewal and differentiation into different cell types. Some daughter cells become absorptive enterocytes, increasing nutrient absorption, while others differentiate into secretory cells that support immunity. Injury and inflammation can disrupt this balance, leading to deficits in secretory cells and compromised gut integrity.

Previous studies have linked this differentiation process to transcription factors and signaling pathways such as WNT, BMP, and Notch. However, the role of metabolism in guiding regenerative responses remained less understood. To investigate, scientists engineered mouse models with inducible capabilities and developed intestinal organoids to explore how metabolic pathways affect cell lineage decisions.

Metabolomic profiling revealed that progenitor cells destined for the secretory pathway had higher levels of citrate, aconitate, and α-ketoglutarate (αKG), while absorptive progenitors exhibited increased ATP and biosynthetic intermediates. Suppressing OGDH activity elevated αKG levels and biased progenitors toward a secretory fate without inducing cell death. Conversely, inhibiting OGDH in absorptive cells hindered proliferation and mitochondrial function.

In vivo experiments demonstrated that supplementing αKG or reducing OGDH activity increased secretory cell populations, including goblet and Paneth cells, and enhanced intestinal tissue repair. During colitis, OGDH expression was found to increase, whereas αKG levels decreased. Interventions that suppressed OGDH or supplemented αKG ameliorated inflammation-induced damage and improved epithelial healing.

These findings suggest that OGDH functions as a metabolic switch, supporting the energy demands of absorptive cells while preventing excessive αKG accumulation in secretory progenitors. By modulating this enzyme, it is possible to influence stem cell fate, enhance secretory cell generation, and promote tissue regeneration during inflammation.

Overall, this research highlights metabolism's role as both a consequence and driver of cell fate decisions. Targeting metabolic pathways like OGDH activity and αKG levels could offer new strategies for treating gastrointestinal diseases characterized by epithelial imbalance and inflammation.

Source: https://medicalxpress.com/news/2025-06-enzymatic-cell-fate-intestinal-regeneration.html