Efficient control of enterochromaffin versus islet differentiation from human pluripotent stem cell-derived pancreatic progenitors

Knowledge of the molecular cues guiding pancreatic development is critical to developing beta cell replacement therapies for the treatment of diabetes. We compare different methods of pancreatic endocrine differentiation from human pluripotent stem cells (hPSCs) and establish sequences of patterning that can selectively increase the frequencies of islet-like or off-target enterochromaffin (EC)-like cells, thereby significantly increasing islet-like cellular yield and glucose-stimulated insulin secretion. Using a model of disrupted murine islet development that gives rise to pancreatic EC-like cells, we identify persistent Neurogenin 3 (NGN3) expression as a conserved feature associated with human and murine pancreatic EC-like cell differentiation. Finally, by comparing the phenotypes obtained through different patterning strategies, we observe that endocrine subtypes can vary significantly in their expression of canonical lineage markers. In addition to expanding our understanding of pancreatic endocrine lineage allocation and identity, these findings establish a logical differentiation framework to guide the generation of designer hPSC-islets for research and therapeutic applications. How different islet lineages emerge within pancreatic islets remains largely unknown. Here, using hPSC and mouse models, the authors identify mechanisms that influence islet versus enterochromaffin lineage specification and islet functionality.