Unsolved mysteries in the intestinal crypt
by Angela C.H. McDonald
The intestine is an amazing organ. In fact, when I am not reading research related to my thesis, I read about the stem cell population that maintains our gut, the intestinal stem cells (ISCs). And sometimes, the reading reveals most unusual mysteries.
ISCs have their work cut out for them. They must renew the lining of our intestines every few days throughout our lives. ISCs reside in a niche located somewhere within the glands that line our gut tissue (also known as intestinal crypts) however; much speculation and controversy has surrounded the exact identity and location of the ISCs.
Back in September a group of researchers reported in Nature that +4 cells are able to repopulate the intestinal epithelium in the absence of crypt base columnar cells. Intriguingly, it was also shown that +4 cells can give rise to crypt base columnar cells, a finding that may suggest that +4 cells are at the top of an ISC hierarchy.
But not so fast – a study published in early November in Science challenges this hypothesis. This team of researchers showed that not only can +4 ISCs give rise to crypt base columnar cells but crypt base columnar cells can also give rise to +4 cells.
Typically, tissue stem cells are less active – or quiescent, dividing infrequently to create one stem cell and one more specialized cell. It was assumed that this predictable behaviour maintains tissue homeostasis within an organ. However, infrequent division does not explain the ability for organs such as the intestine to renew as often as they do.
Researchers previously speculated that quiescent and active stem cells have complementary functions within the tissue, in which the rapidly cycling stem cells would renew tissue while a quiescent stem cell pool would divide on a rare occasion to replace rapidly cycling stem cells.
If this is the case, the question is: why are rapidly cycling crypt base columnar cells capable of giving rise to quiescent +4 cells, especially if that ability is not required as part of normal tissue function? Perhaps this is a stem cell back-up system, another way to ensure long-term maintenance and regenerative capacity of a tissue.
Interestingly, the intestine isn’t the only tissue in which quiescent and fast cycling stem cell populations have been shown to coexist. Similar stem cell behaviour has been observed in the blood and hair follicle systems. In the hair follicle, regeneration is initiated by active hair germ stem cells. These cells arise from quiescent bulge stem cells and are more efficient at responding to regenerative cues; however, they are shorter-lived than bulge stem cells. This suggests that active stem cells initiate regeneration, whereas quiescent stem cells maintain the regenerative capacity of the hair follicle.
While we seem to understand the relationship between quiescent and active stem cells in the hair follicle, as demonstrated by recent publications, we have yet to unravel the exact nature of this relationship in the gut.