Mechanisms involved in specifying and determining the different pancreatic cell types: cell plasticity and regeneration by cell type interconversion
We study the mechanisms of cell fate allocation and specification for the different pancreatic cell types, both during ontogeny and during pancreas regeneration in the diabetic adult. In particular, we are interested in understanding the origin of insulin-producing β-cells. These studies are performed through the generation of different strains of transgenic mice. There are three main areas of research:
- determination of cell fates,
- establishment of islet cell lineages,
- differentiation / regeneration potential of adult pancreatic cells.
The cell lineages of the islets of Langerhans are studied in mice bearing simultaneously several transgenes. Using the Cre / loxP system we tag cells in vivo, either in embryos or adults. We can irreversibly mark precursor or hormone-producing cells through site-specific recombination mediated by Cre recombinase. Reporter gene expression is therefore dependent upon Cre activity in particular cell types.
Cell fate decisions in early pancreatic primordia are taken through cell autonomous and cell non-autonomous signals. We analyze the role of different effectors of signaling pathways in different conditional transgenic mice.
The regeneration potential of adult pancreata is studied with different approaches. New transgenic mice in which specific pancreatic cell types can be conditionally ablated are used to analyze the process of β-cell reconstitution after injury, so as to determine the extent and mechanisms of β-cell regeneration in the adult pancreas, at different ages.
We have recently reported that an extreme β-cell loss in adult mice is followed by a process of spontaneous β-cell regeneration, which mostly relies on the direct reprogramming of adult glucagon-producing α-cells into insulin-producers, among other islet cell type interconversion events. We have also observed that a very limited number of α-cells is sufficient to prevent any major metabolic deregulation in basal conditions in adult mice.