Abstract
Pancreas organogenesis relies on sequential interactions between the pancreatic epithelium and surrounding mesodermal cell types that initiate epithelial budding and branching to form a complex ductal network with terminal acini. Despite recent advances with pluripotent stem cell-based approaches, there are no models that robustly recapitulate pancreas morphogenesis or the spatial organization of ductal, exocrine, endocrine and mesenchymal cells seen in the native organ. Here, we introduce a new pluripotent stem cell-based pancreatic organoid that captures the complexity seen during pancreatic development, with budding and stratification of multipotent progenitors followed by formation of a ductal network that give rise to peripheral acini. We identify a critical role for mesenchyme-derived factors to robustly promote pancreatic organoid formation and morphogenesis. Human pancreatic organoids are correctly patterned, with functional exocrine acini secreting digestive enzymes into a ductal network. Comparative analysis confirms that the pancreatic organoids are similar to early second trimester human pancreas, with potential to further mature upon transplantation in mice. Finally, we show that endocrinogenesis can be reproduced in organoids, generating functional islet-like clusters interspersed within the ductal network. Together, this represents an exciting new platform to study human pancreas development and a broad array of pancreatic diseases.