Instead, Paneth cells provide growth factors, like Wnt, and create the right conditions for stem cells to survive and divide. But in the intestine, there is no little scientist providing growth factors. "In organoid culture, we scientists provide growth factors, so the knockout of both Rnf43 and Daam1 lead to tumor-like organoids. This link between the molecular results and Paneth cells explains the puzzling difference between intestines and organoids. When Daam1 is not active, the stem cells differentiate into another cell type." When Daam1 is active, stem cells differentiate to form Paneth cells. "Daam1 is required for the efficient formation of Paneth cells. Paneth cells secrete growth factors, such as Wnt, that stimulate cell division. Intestines lacking Daam1, on the other hand, contained no extra Paneth cells. Looking closely at the intestines, Colozza saw that intestines lacking Rnf43 were full of a specific type of secretory cells, the Paneth cells. We were puzzled by this striking difference: how can the loss of factors in the same pathway, that behave similarly in organoids, lead to such different outcomes?" But when Daam1 was missing, no tumors grew. "When Rnf43 was missing, the intestines grew tumors - as expected. When Colozza followed up this result in mouse tissue, the researchers were in for a surprise. These tumor-like organoids keep on growing, even if we withdraw the growth factors they usually depend on, such as R-spondin." "We found that when we knock-out Rnf43 or Daam1, the organoids grow into tumor-like structures. For Colozza, organoids were an opportunity to understand how Rnf43 and Daam1 affect the delicate balance of stem cell renewal and differentiation in the intestine. Intestinal organoids are three-dimensional cell cultures grown from adult intestinal stem cells, allowing the researchers to mimic the intestinal mucosa. From the endosomes, Frizzled is shuttled to the lysosomes where it is degraded, dampening Wnt signaling," Colozza adds. Further work in cells showed Rnf43 needs Daam1 to move the Wnt receptor Frizzled into vesicles called endosomes. "We found that Daam1 is required for Rnf43 to be active, so for Rnf43 to regulate Wnt signaling at all. To understand how Daam1 regulates Rnf43 and affects the tissues it acts in, Colozza turned to intestinal organoids. "In our project, we used biochemical assays to identify which proteins interact with Rnf43." A key partner of Rnf43 turned out to be the protein Daam1. "We wanted to know how Rnf43 works, and also what - in turn - controls Rnf43 and helps it to regulate Wnt signalling." From earlier research, the scientists knew that Rnf43 on its own was not sufficient to break down the Wnt receptor Frizzled, which sits in the plasma membrane. Prior to this study, Rnf43 was known to target the Wnt receptor Frizzled and mark it for degradation. The Wnt pathway is known for its role in embryonic development, and if left unchecked, an overactive Wnt pathway can lead to excessive cell division and the formation of tumors.Ī well-known antagonist of Wnt signalling - keeping Wnt in check - is Rnf43, which was originally identified by Bon-Kyoung Koo. This balance is delicately tuned by signaling pathways and feedback loops, which allow cells to communicate with each other. "Damaged cells have to be replaced, but it is a delicate balance between stem cell renewal and differentiation into other cell types: uncontrolled stem cell proliferation may lead to tumor formation on the other hand, if too many stem cells differentiate, the tissue will be depleted of stem cells and ultimately unable to self-renew." In turn, stem cells in the intestine's mucosa differentiate to form new intestinal cells. Mechanical wear and tear, but also digestive enzymes and varying pH values all affect intestinal cells. "In our intestines, cells are exposed to extreme conditions," Colozza explains. Intestines - a constant construction site But how do tissue-specific stem cells know which cell type to give rise to? Gabriele Colozza, a postdoctoral researcher in the lab of Bon-Kyoung Koo at IMBA - now director at the Center for Genome Engineering, Institute for Basic Science in South Korea - decided to investigate this question using intestinal stem cells. In contrast with embryonic stem cells, which can form any cell type in the body, adult stem cells will only form the cell types that are found in the tissue they belong to. This replacement occurs thanks to tissue-resident adult stem cells. In the case of our bodies, any cells that are damaged or dead need to be replaced to keep organs functioning. Our bodies are, in some ways, like cars - to keep functioning, they need to be checked and repaired regularly.
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