Stromal and Neuronal Sources of Slit2/3 Ligands in the Adult Pancreas Exhibit Distinct Expression Patterns Independent of Robo2 Receptor Expression in the Islet

Abstract

Pancreatic islets regulate blood glucose homeostasis. Although islet architecture is stable under homeostatic conditions, increased metabolic demand drives compensatory islet expansion. In mice, islets are organized as a {beta} cell core surrounded by a mantle of and {delta} cells. The formation of islet architecture during development requires expression of Roundabout receptors 1 and 2 (Robo1/2) in endocrine cells and of Slits 2 and 3 (Slit2/3) from islet-extrinsic sources. Furthermore, expression of Robo2 in endocrine cells is required to maintain islet architecture in the adult mouse. However, the cellular sources of Slit2/3 in the adult pancreas and their expression dynamics during islet expansion remain unknown. Here, we identify distinct stromal populations, including fibroblasts and pericytes, as well as neurons within intrapancreatic ganglia, as the sources of Slit2/3. We further show that Slit3 expression is increased in Ob/Ob mice, and that SLIT2 expression is elevated in stromal cell populations of humans with type 2 diabetes. The expression of neither Slit2 nor Slit3 was affected by deletion of Robo2 in {beta} cells. Together, these findings define the cellular origins of Slit2/3 and their expression dynamics in the adult pancreas, supporting a potential role for Slit signaling in the diabetic islet microenvironment.