IFN Signaling Regulation Preserves Intestinal Stem Cells Stemness

Researchers from Tokyo Medical and Dental University have identified a novel molecular mechanism that preserves the stemness of intestinal stem cells. Their study was published in Nature. 

"Just like any other type of stem cell, intestinal stem cells have the ability to differentiate into any cell within their lineage," says corresponding author Toshiaki Ohteki. "But they have to do it in a regulated manner, only differentiating when needed. The goal of our study was to understand the regulatory mechanism that preserves the stemness of intestinal stem cells."

In order to understand these regulatory mechanisms, they focused on a molecular signaling pathway that had been previously shown to preserve the stemness of hematopoietic stem cells that give rise to blood cells. Interferons catalyze the expression of certain genes—regulated by the protein interferon regulatory factor-2 (IRF2)—and in the case of HSCs, IRF2 was found to play a crucial role in their stemness.

The team discovered that IRF2 is produced throughout the intestinal epithelium and that IRF2-deficient mice had normal anatomical structure during homeostasis. They also observed that in the presence of 5-fluorouracil—which is known to damage the intestinal epithelium—control group mice were able to regenerate completely, while IRF2-deficient mice showed a stunted regenerative response. These findings confirm that intestinal stem cells are not able to function properly in the absence of IRF2. 

"These are striking results that show how excess interferon signaling in the absence of IRF2 impairs the ability to self-renew and directs intestinal stem cells towards the secretory cell lineage. Our findings provide new insight into the biology of intestinal stem cells and show that regulated interferon signaling is a means to preserve the stemness of intestinal stem cells," Ohteki concludes.