MACBETh: Uncovering the role of MACrophages in BETa cell (re)generation.

Diabetes is a pandemic metabolic disease characterized by dysfunction or loss of the insulinproducing pancreatic beta cells. Most people with diabetes are treated with oral antidiabetic drugs or
injectables (GLP-1 analogs or insulin). However, this approach is burdensome and fails to completely
prevent hyperglycemia-related complications. Beta cell replacement through regeneration of the
endogenous beta cell mass offers an attractive alternative with a curative perspective. However, the
signals that drive beta cell regeneration remain elusive. Islet-resident macrophages were originally
considered detrimental to beta cell survival and function, but as their heterogeneity is increasingly
appreciated, islet-resident macrophages may even be involved in regulating beta cell (re)generation.
With this project, I will use cutting-edge technologies, including CITE-Seq, high-parameter
multicolour flow cytometry, RNA in situ hybridisation, whole-organ 3D imaging, as well as innovative
loss-and gain-of-function approaches to comprehensively characterize the heterogeneity and role of
islet macrophages during mouse pregnancy, a robust model of adult beta cell proliferation. Nonpregnant female and male mice will serve as controls to additionally explore sexual dimorphism in
beta cells and macrophages. This project aims to validate islet macrophages as novel targets and
tools for the development of innovative beta cell regeneration strategies