From architecture to function: mechanisms shaping pancreatic islet morphogenesis.

Islets of Langerhans are highly structured mini-organs containing hormone-producing cells of the pancreas that regulate glucose metabolism. Studies of endocrine cell differentiation and clustering into immature proto-islets, as well as remodeling into mature islets, are beginning to clarify the critical timepoints and mechanisms governing islet formation across species. In this review, we compare the mechanistic features of the current models of islet morphogenesis, linking them to established intrinsic and extrinsic signals. These signals coordinate endocrine cell differentiation, migration, and clustering to form a distinct 3D islet architecture, while their disruption leads to islet dysfunction. Understanding 3D islet morphogenesis will enable the generation of mature stem cell-derived islets for regenerative therapies and help identify druggable pathways to restore islet function in diabetes.