Determinants and dynamics of pancreatic islet architecture

Abstract

The islets of Langerhans are highly organized structures that have species-specific, three-dimensional tissue architecture. Islet architecture is critical for proper hormone secretion in response to nutritional stimuli. Islet architecture is disrupted in all types of diabetes mellitus and in cadaveric islets for transplantation during isolation, culture, and perfusion, limiting patient outcomes. Moreover, recapitulating native islet architecture remains a key challenge for in vitro generation of islets from stem cells. In this review, we discuss work that has led to the current understanding of determinants of pancreatic islet architecture, and how this architecture is maintained or disrupted during tissue remodeling in response to normal and pathological metabolic changes. We further discuss both empirical and modeling data that highlight the importance of islet architecture for islet function.

Keywords: Islets of Langerhans; diabetes; islet architecture; islet development; islet morphogenesis.

Figure 1.

Stages and determinants of islet morphogenesis: Egression, clustering, and differentiation: Neurog3 high endocrine progenitors egress from the bipotential epithelial cord in clusters that differentiate into islet endocrine cells while remaining attached and adjacent to this cord. Nerves and blood vessels closely associate with these clusters early on, possibly providing morphogenetic signals. Fusion and endocrine cell type segregation: Endocrine cells expand and fuse to adjacent clusters, creating long strings of primitive islet structures along the ducts. These structures have segregated endocrine cell types and are surrounded by extra-islet nerves, ascinar tissue, and mesenchyme, which provide morphogenetic signals. Blood vessels now penetrate the islet via mutual attraction of endothelial and β cells. Fission and migration away from ducts: Elongated islet structures and size of adult islets. Extra-islet nerves have invaded the islet through scaffolding with intra-islet vasculature, and β cells have reached maturity. Islet endocrine cell type segregation is maintained throughout homeostatic adulthood. β celll rosette: β cells within the islet organize into rosette structures around blood vessels with their cilia projecting into the extracellular space, though timing and morphogenesis of this organization is unknown. Figure created by Biorender.com.