Fig. 7: A summary of three concepts for islet formation and morphogenesis.

Schematic of three concepts for islet formation and morphogenesis, both in vitro (a–c) and in vivo (d–f). The budding peninsula theory (e) proposes that islet peninsulas form through coordinated migration and budding of endocrine-committed cells, which emerge from a network of epithelial tubules, or “cords,” and remain attached to the outer layer. Therefore, peninsular growth relies on continuous recruitment of newly-formed endocrine-committed cells from epithelial cords. In the dispersal-aggregation model (f), individual endocrine precursor cells migrate away from epithelial cords via an EMT process and disperse into surrounding mesenchyme. As cells differentiate and acquire an islet cell fate, they are thought to aggregate into small clusters that later constitute complete islets. In our differentiating stem cell model, we reveal that a vast majority of PDX1+ cells undergo clustering and budding out from PDX1-negative main bodies prior to endocrine specification. With our media highly enriched with endocrine cell-directed cocktails (which inhibits progenitor cell proliferation and does not support ductal/exocrine commitment) at later stages, these hormone-negative, PDX1+ progenitor cells migrate together in an EphB3/4 signaling dependent manner, and once aggregated, the PDX1+ pancreatic bud efficiently gives rise to an endocrine islet while only a certain population of PDX1+ progenitor cells (very likely the ones with high PDX1 expression level) are specified to islet cells within the bud (a). This paradigm is supported by observations of islet formation in fish and lamprey, where a dorsal bud is formed through the convergence of PDX1+ cells that later develop into a principal islet (d). Created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license in (a–f).