Mother cells control daughter cell proliferation in intestinal organoids to minimize proliferation fluctuations.

The vast majority of cells lining our intestine die within three to five days. They are replaced by a small group of stem cells which divide to produce either more stem cells, or cells that stop dividing and transform, or 'differentiate', in to mature cells in the intestine. Stem cells must generate the same number of dividing and differentiated cells. If there is even a slight bias and too many stem cells are produced, this can lead to uncontrolled growth, which is the root cause of cancer. In principal, the best way to achieve this balance is for stem cells to always asymmetrically divide in to two distinct cells: one that will continue to divide, and another that will mature in to an adult cell. However, recent research suggests that this process is much more random, with stem cells also dividing symmetrically, either in to two stem cells or two differentiated cells. So, how does the random nature of stem cell divisions not cause the number of dividing cells to fluctuate unpredictably in the intestine? To investigate, Huelsz-Prince et al. studied stem cells in a miniature model of the mouse intestine, known as an organoid, which can be grown outside of the body in a laboratory. All stem cells and their progeny were tracked for over 65 hours using a microscope to see how many dividing and differentiated cells they formed. This revealed that almost all stem cells in the organoid split symmetrically rather than asymmetrically. Huelsz-Prince et al. then developed a computer model of stem cells in the model intestine and tested the impact of changing the proportion of symmetric and asymmetric divisions. The results showed that having more symmetric divisions reduced fluctuations in the number of dividing cells better than high levels of asymmetric divisions. Other organs rely on a similar system to the intestine to replenish their mature cells. Consequently, the finding that symmetric divisions control fluctuations in the number of stem cells may be applicable to other parts of the body. Further testing with human disease samples, such as cells from cancer patients, using the organoid model system may also shed light on how division is disrupted in these conditions.