Production and use of functional pancreatic endocrine cell lines – DiabEndoLine

Islets of Langerhans are micro-organs scattered throughout the pancreas and made up of beta, alpha, delta, PP and epsilon cells, which secrete insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Our knowledge of beta cells has exploded thanks to the many models that have allowed their study: preparations of mouse and human islets allowing their study in vitro, transgenic mouse models, murine beta cell lines and more recently human beta cell lines. On the other hand, our knowledge of other pancreatic endocrine cell types remains extremely limited. This is due to the low frequency of alpha, delta and PP cells in the islet, the difficulty in preparing them in numbers, but also the lack of tools to study them. For example, while many beta cell lines have been generated and used over the past 40 years, it is not the case with alpha, delta, and PP cells. This lack of tools generates, despite the data in the literature suggesting an important role of alpha and delta cells in diabetes, an extremely beta-centric view of diabetes. We recently developed a procedure based on an original approach of targeted oncogenesis, which allowed us to generate the first functional human beta cell lines. In this new project, we will use this unique expertise to generate alpha, delta and PP cell lines. The project is subdivided into 3 tasks: i). Production of alpha, delta and PP cell lines using approaches very similar to those we have developed to generate beta cell lines; ii). Characterization of these lines using our expertise acquired for the study of endocrine pancreatic cells; iii). Use of these cell lines to study alpha, delta and PP cells under conditions mimicking diabetes using models that we have recently developed. This project represents a collaboration between two teams (R Scharfmann, INSERM, Institut Cochin, Paris and G Gradwohl, INSERM, IGBMC, Illkirch) which have synergistic expertise within the framework of this project and which have interacted repeatedly in the past. These lines will be shared in a non-restrictive manner with the academic scientific community and will represent unique tools for better understanding the role of alpha, delta and PP cells in physiology and in diabetes.