Epigenetic transcriptional control of intestinal epithelial regionality
General Genetics and Functional Genome Biology
Gastroenterology
Final Report Abstract
Self-renewing tissues such as the inner lining of the intestine (intestinal epithelial cells) depend on the activity of tissue-specific intestinal stem cells (ISCs). These are responsible for the entire epithelial surface to be self-renewed within 5-7 days. The capacity of ISCs to proliferate depends on the microenvironment surrounding them. If the balance of this microenvironment is disrupted, it may lead to conditions such as colon cancer. Therefore, it is crucial to comprehend the functions and logic of this "stem cell niche". Our current understanding of the components of this niche is limited. The surrounding tissue cells, known as "fibroblasts," provide growth factors, but the exact details have remained elusive. Recently, the host laboratory of my postdoctoral fellowship has unraveled a specific component of the stem cell niche: Trophocytes are cells situated beneath the mucosal muscle layer and produce essential hormones. However, the majority of other fibroblasts were still poorly defined. In this fellowship supported by the DFG, I was able to describe how a large proportion of fibroblasts are intrinsically organized, thereby maintaining the balance between growth-promoting and differentiation-promoting factors. My research leveraged the new technology of single-cell RNA sequencing to decipher the gene expression patterns of different types of fibroblasts. My analyses revealed that fibroblasts primarily belong to three defined subtypes. Firstly, specific fibroblasts secreting molecules that promote epithelial cell differentiation. The second group is formed by trophocytes. My project focused on the third group of thus far unknown function. My studies showed that these cells produce Wnt proteins, which are essential for maintaining stem cells. This surprising finding contradicted a previous study. Therefore, I validated my findings with functional in vitro assays in which fibroblasts and intestinal stem cell structures (so-called "organoids") were co-cultured. In microscopic studies, I could then determine the localization of fibroblasts that express specific marker molecules. In this context, I made another discovery: when fibroblasts were stimulated with a particular hormone, they altered their niche behavior. This phenomenon allows the stem cell niche to self-organize and maintain its functionally heterogeneous architecture. The results of this study contribute to a better understanding of the intestinal stem cell niche and demonstrate how various cell types and signaling pathways collaborate to maintain stem cell function. These insights could lead to novel therapeutic approaches aimed at modulating intestinal stem cell regulation and treating diseases such as colon cancer.
Publications
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Cellular and molecular architecture of the intestinal stem cell niche. Nature Cell Biology, 22(9), 1033-1041.
McCarthy, Neil; Kraiczy, Judith & Shivdasani, Ramesh A.
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SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling. Cell Stem Cell, 29(1), 101-115.e10.
Gu, Wei; Wang, Hua; Huang, Xiaofeng; Kraiczy, Judith; Singh, Pratik N.P.; Ng, Charles; Dagdeviren, Sezin; Houghton, Sean; Pellon-Cardenas, Oscar; Lan, Ying; Nie, Yaohui; Zhang, Jiaoyue; Banerjee, Kushal K.; Onufer, Emily J.; Warner, Brad W.; Spence, Jason; Scherl, Ellen; Rafii, Shahin; Lee, Richard T. ... & Zhou, Qiao
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Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche. Cell Stem Cell, 30(4), 433-449.e8.
Kraiczy, Judith; McCarthy, Neil; Malagola, Ermanno; Tie, Guodong; Madha, Shariq; Boffelli, Dario; Wagner, Daniel E.; Wang, Timothy C. & Shivdasani, Ramesh A.
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Smooth muscle contributes to the development and function of a layered intestinal stem cell niche. Developmental Cell, 58(7), 550-564.e6.
McCarthy, Neil; Tie, Guodong; Madha, Shariq; He, Ruiyang; Kraiczy, Judith; Maglieri, Adrianna & Shivdasani, Ramesh A.
