Generation And Characterization Of A Novel Mouse Model That Allows Spatiotemporal Quantification Of Pancreatic Beta-Cell Proliferation

Pancreatic beta-cell proliferation has been gaining much attention as a therapeutic target for the prevention and treatment of diabetes. In order to evaluate potential beta-cell mitogens, accurate and reliable methods for the detection and quantification of the beta-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating beta-cells as mVenus(+)cells by using RIP-Cre; R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in beta-cells. In response to beta-cell proliferation stimuli, such as insulin receptor antagonist S961 and diet-induced obesity (DIO), the number of 5-ethynyl-2 '-deoxyuridine-positive insulin(+)cells per insulin(+)cells and the number of mVenus(+)cells per mCherry(+)mVenus(-)cells + mCherry(-)mVenus(+)cells were similarly increased in these mice. Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled quantification of replicating beta-cells in the islets and morphometric analysis of the islets after known mitogenic interventions such as S961, DIO, pregnancy, and partial pancreatectomy. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis and quantification of beta-cell proliferation in response to mitogenic stimulation.