Directed differentiation of pancreatic δ cells from human pluripotent stem cells

Dysfunction of pancreatic delta cells contributes to the etiology of diabetes. Despite their important role, human delta cells are scarce, limiting physiological studies and drug discovery targeting delta cells. To date, no directed delta-cell differentiation method has been established. Here, we demonstrate that fibroblast growth factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic delta-cell lineage via FGF receptor 1. We develop a differentiation method to generate delta cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These delta cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress insulin secretion from in vitro co-cultured beta cells and mouse beta cells upon transplantation. The generation of human pancreatic delta cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes. Human pancreatic delta cells play important roles in the balance of pancreatic hormones. Here, the authors develop a directed differentiation method to generate in vitro and in vivo functional delta cells from human stem cells by combining FGF2 with FGF7.