Researchers at the Organoid Group (formerly the Clevers Group) have improved human small intestinal organoids – miniature versions of the small intestine. This will help them better study the functioning of the small intestine during health and disease. Specifically, the researchers succeeded in developing organoids containing mature Paneth cells, which were not present in previous human small intestinal organoids. The results of the study were published August 23 in Cell Stem Cell.
The development of organoids has meant a lot for research into the functioning of human organs and tissues. This has to do with the fact that mini-organs give a good representation of human biology. However, some of the currently available human organoids, such as small intestinal organoids, still do not fully resemble the original organ. Therefore, researchers in the Organoid group developed a new, optimized version of the small intestine in miniature: organoids that include all cell types in the human small intestine.
Paneth cells are absent
The small intestine contains a wide variety of cells, including enterocytes, stem cells, and Paneth cells. Together, these cells form a barrier between the side where food passes and the side where blood vessels and immune cells are. The stem cells in the small intestine continuously create all types of mature cells, thus keeping the barrier in good shape. In particular, Paneth cells are important in preventing infections. They do this by producing antimicrobial peptides that act against harmful bacteria. If there are no active Paneth cells, the small intestine will be more prone to infections. This is a problem in several diseases, including inflammatory bowel disease (IBD). The above organoids lacked Paneth cells and therefore did not fully represent the healthy human small intestine, whereas the original mouse organoids described by Toshi Sato in Nature (2009) were complete. This indicated that there was room for improvement in human organoids.
Surprising find
To induce the formation of Paneth cells in human small intestinal organoids, the researchers studied the effect of several molecules. They discovered that the molecule interleukin-22 (IL-22) increased the number and activity of Paneth cells. The effect of IL-22 on Paneth cells is surprising. Researcher Gui-Wei He explains why: “Currently, people believe that IL-22 can promote stem cell function. Our study actually showed that IL-22 does not do this, but which stimulates the activation of Paneth cells”. Therefore, the discovered function of IL-22 was used to increase the number of active Paneth cells in human small intestinal organoids. This led to the development of organoids that mimic the healthy small intestine.
Future directions
Now that optimized human small intestinal organoids are available, researchers can expand what they study. For example, researchers can use the organoids to make mutations in the cells’ DNA. In this way, they can determine how mutations – which occur in diseases such as IBD – affect the function of the small intestine.
Source:
Journal reference:
He, GW., et al. (2022) Optimized human intestinal organoid model reveals interleukin-22 dependence of Paneth cell formation. Cellular stem cell. doi.org/10.1016/j.stem.2022.08.002.