Deciphering mechanisms of pancreatic β cell homeostasis and regeneration

• Applicants: Professor Dr. Heiko Lickert; Professor Dr. Fabian Theis; Professor Dr. Eckhard Wolf
• Subject Area: Gastroenterology ; Bioinformatics and Theoretical Biology ; Endocrinology, Diabetology, Metabolism ; Developmental Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458958943

Currently, no treatment can cure diabetes mellitus, a multifactorial metabolic disease characterized by the loss or dysfunction of insulin-producing ß cells in the islets of Langerhans. Novel therapies triggering endogenous regeneration of functional β cell mass hold great promises for improved diabetes treatment. New β cells can be generated via self-replication of pre-existing ß cells in islets and via neogenesis from progenitors, which occur early postnatally but rarely in adulthood as shown in in vitro and in mouse models. Our recent studies suggest that ß cell replication and neogenesis occur in postnatal and adult pig. Contrary to small animal rodents, pig is a large animal model with a longer lifespan and shares physiological similarities to human, and is thus a better model system for clinical translation. In this project we will use pig models to test the hypothesis that ß cell homeostasis and regeneration can be sustained continuously by β cell replication and neogenesis throughout life.The goals of this project proposal are: (Objective 1) to define the spatiotemporal transcriptional dynamics of the specialized regions (niches) comprised by ß, ductal and acinar cells, which potentially influence β cell replication and neogenesis via cell-to-cell communication, and (Objective 2) to dissect the cell type-specific gene regulatory networks and identify surface markers of the heterogeneous subpopulations of ß, ductal and acinar cells that contribute to ß cell replication and neogenesis. These objectives will be achieved by using advanced single-cell multimodal omics tools, which allow the profiling of transcriptome signatures with spatial position (spatial transcriptomics) and, simultaneously, the analysis of epigenomes, transcriptomes and epitopes (CITE-seq coupled with scATAC-seq) of ß, ductal and acinar cells in the pancreas. Our project will clarify the paths and mechanisms of ß cell homeostasis and regeneration using pig models and will provide novel pharmacological targets for ß cell regenerative therapy.

• DFG Programme: Research Grants