Deciphering functional heterogeneity within the embryonic intestinal stem cell progenitors in health and disease

• Applicant: Dr. Natalia Soshnikova
• Subject Area: Developmental Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427330905

The small intestinal epithelium has a number of vital functions, including absorption of nutrients, secretion of hormones and host defence against microorganisms. To support its diverse functions, Intestinal Stem Cells (ISCs) generate and maintain functionally distinct types of differentiated epithelial cells. A balance between ISC proliferation and differentiation is tightly regulated, as an excessive proliferation leads to tumorigenesis. In healthy gut epithelium, ISCs display different molecular characteristics according to their position along the anterior-posterior axis. In inflammatory bowel disease (IBD), ulcerative colitis and Crohn disease patients, molecularly different types of ISCs are combined within the same region. It remains unknown whether ISCs are functionally heterogeneous within the same segment of the gut. If yes, do they form distinct functional units according to their embryonic origin?Recently, we showed that the embryonic gut epithelium is composed of molecularly heterogeneous ISC progenitors. Now, we aim to establish a functional role for this heterogeneity during gut development. We will genetically eliminate a specific ISC progenitor population in embryo to define whether these cells have distinct, unique functions for gut patterning and morphogenesis. Moreover, using 3D organoid assays we will examine a capacity of various embryonic ISC progenitors to generate adult ISCs ex vivo. Our second aim is to determine whether molecularly distinct embryonic ISC progenitors give rise to functionally distinct adult stem cells, including cancer stem cells. Using a combination of single cell RNA-sequencing, spatial mapping and genetic lineage tracing analyses we will follow fates of various embryonic ISC progenitors during healthy homeostasis and neoplastic transformation of the gut epithelium. Finally, using pharmacological inhibitors, we will identify signals required for the specification and maintenance of various ISC progenitors during embryogenesis.The results of this project will generate knowledge essential for understanding mechanisms inducing neoplastic transformation and chronic inflammatory diseases, such as IBD and Crohn disease. Our data may provide important clues into the cells and molecular networks operating within each type of ISC progenitors that are most relevant to development of these diseases.

• DFG Programme: Research Grants