Stem Cell-Derived Organoids of the Pancreas: Evaluation of Endocrine and Exocrine Modeling Platforms

As miniature, three-dimensional emulates of individual human organs generated in vitro, organoids are increasingly recognized as complex, humanized models of development, disease, diagnostics, and drug discovery. Organoids exhibit organ-specific architecture, function, and multicellular composition, can be infinitely derived from pluripotent stem cells, and can be further directed toward organoids of the endocrine or exocrine pancreas. Pancreatic endocrine organoids are rapidly redefining diabetes therapies due to their ability to recapitulate glucose-responsive insulin secretion. Conversely, there is less focus on pancreatic exocrine organoids, which possess untapped potential for investigating disorders such as cancer and cystic fibrosis. This review first summarizes human pancreatic organogenesis to contextualize relevant differentiation pathways, then details protocols that guide human pluripotent stem cells through key developmental stages. Methods to enhance cellular maturation and establish higher-performing end products, as well as the therapeutic value of different pancreatic genres, are assessed. Furthermore, crucial gaps are identified, including limited insight into non-beta-endocrine cells, progenitor lineage bias, and off-target differentiation. By chronicling the advancements of all pancreatic organoid classes, the importance of creating more intricate constructs is underscored, which could lead to their broader application.AbstractImpact StatementThis review consolidates foundational work and recent advances in the generation and engineering of pancreatic organoids from human pluripotent stem cells, providing a comprehensive analysis of both endocrine and exocrine cell lineage development. Current differentiation protocols and the associated engineering innovations that improve the maturity of stem cell derivatives are evaluated. The review underscores the growing potential of organoids in disease modeling, drug discovery, and regenerative medicine. Emphasizing the need to expand the functional scope of organoids beyond β-cell-centric models is crucial for future efforts to develop physiologically complex and more clinically relevant pancreatic tissue equivalents.