Pancreatic islets were previously thought to assemble away from pancreatic ducts via a dispersal-aggregation model. Research published in Cell reveals a new model of islet morphogenesis in which α-cells and β-cells form layered peninsular structures.

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“We performed this study to get a detailed understanding of how pancreatic islets form,” explains corresponding author Douglas Melton. “This information could help us in our quest to generate pancreatic islets from human stem cells.”

The researchers mapped early pancreatic islet formation in pancreata extracted from neurogenin 3 (a marker of endocrine differentiation; NGN3)–eGFP reporter mice embryos using single cell RNA sequencing. Importantly, α-cells appeared earlier than β-cells in this model, which is consistent with previous reports.

Novel methods of statistical analyses developed by the team were used to track the developmental fate of NGN3+ cells and to model temporal gene expression programmes. Notably, undifferentiated, early cells have an endocrine-progenitor gene expression programme and the onset of cell specification is marked by a switch to a pan-endocrine expression programme. Following this, differentiating islet cells show a gradual accumulation of cell-specific gene expression programmes

Using immunostaining and tissue clearing, the researchers visualized embryonic pancreata in 3D. Strikingly, endocrine progenitors were seen to form budding peninsula shapes, which grow over time, with older cells being pushed outwards by newer cells. The peninsulas form a layered structure that faces away from epithelial cords, with α-cells lying on top of β-cells.

Finally, the researchers generated similar human endocrine peninsula-like structures in vitro by directing the differentiation programmes of human embryonic stem cells.

Strikingly, endocrine progenitors were seen to form budding peninsula shapes

“These findings provide hints about how to improve the production of islet cells from human stem cells,” concludes Melton. “The results indicate the order in which cells appear from progenitors, the temporal expression of some key genes and the physical arrangements of cells within a mature islet.”