Cells in the intestine need to be replaced continuously as they are worn down by food processing. This is enabled by a reservoir of stem cells located in crypts at the base of the villi, finger-like projections in the intestine that absorb nutrients.

These stem cells either continue replicating in the crypts or move up to become ‘transit-amplifying cells’ (TA cells), which can produce the specialised cells at the tip of the villi.

Within the population of TA cells, a balance needs to be kept between producing more TA cells and allowing these cells to mature into specialised cells for food processing. If this ratio is imbalanced, the intestine can’t repair itself efficiently after injury.

In research published in the Journal of Experimental Medicine, scientists at the Crick identified that a gene called Arid3a controls this balance in the mouse intestine.  

This gene codes for the ARID3A protein, which works by applying the brakes on TA cell specialisation. This allows some TA cells to replicate in the crypts and therefore maintain the reservoir.

When the scientists removed the Arid3a gene from mice, more specialised cells were identified at the top of the villi, suggesting that the balance was tipped in favour of specialisation rather than TA cell production.

This wasn’t a big problem in healthy mice, but mice with intestines damaged by irradiation weren’t able to repair the damaged cells efficiently in their intestines. This was because the lack of ARID3A meant there weren’t enough TA cells ready to replace the damaged ones.

Vivian Li, group leader of the Stem Cell and Cancer Biology Laboratory at the Crick, and senior author, said: “We’ve identified the control gene for this decision moment: whether to keep producing more cells or to allow these cells to commit to their fate – a fine-tuned balance which is crucial to repair the gut and keep it functional.

“Diseases affecting the gut in humans, like inflammatory bowel disease, can involve a chronic state of injury, so it would be interesting to explore whether Arid3a also plays a role in preventing the human gut from repairing itself.”

Nikos Angelis, former PhD student in the Stem Cell and Cancer Biology Laboratory, and co-first author with Anna Baulies, said: "The intestinal epithelium is a truly fascinating system for stem cell biology. Understanding the complex mechanisms that allow its rapid regeneration has been extensively studied over the past few decades; yet, our work adds one more layer of complexity. We showed that Arid3a is central to the intestinal recovery process and that its loss increases the differentiation capability of transit-amplifying cells and ultimately affects the gut's capacity to regenerate."

The next step for the research is to gain a full picture of the stem cell to TA cell transition by defining the TA cell population’s gene regulatory network: all the molecules that come together to switch genes on or off. This is important for understanding how the stem cell reservoir is maintained, which in turn will improve understanding of the tissue repair process during damage in the intestine from irradiation and inflammation.

Vivian and the team worked with the Genomics, Experimental Histopathology, Bioinformatics and Biostatistics and Advanced Light Microscopy teams at the Crick.