human embryonic stem cell-dervied islet organoid sequencing

Human pancreatic delta cells maintain the balance of hormones from the pancreas and loss of delta cells or disturbance of somatostatin release is associated with diabetes. Despite their important role, human delta cells are scarce, which limits physiological studies and drug discovery targeting delta cells. To date, no directed delta-cell differentiation method has been established. In this study, we established a link between fibroblast growth factors (FGFs) signaling pathways and pancreatic delta-cell lineage specification. FGF7 helped maintain a pancreatic endoderm/progenitor state with higher expression levels of PDX1 and CHGA, while FGF2 biased cells toward pancreatic delta-cell lineage by inducing the expression of SST and delta-cell specific transcription factor HHEX, via FGF receptor 1(FGFR1). Thereby, we developed a robust differentiation method for generating delta cells from human stem cells by the combination of FGF2 with FGF7, which synergistically modulates transcription factor expression during endoderm/endocrine precursor induction. These delta cells display matured RNA profiles and suppressed insulin secretion from co-cultured beta-cells. The generation of somatostatin-secreting pancreatic delta cells from human stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation study in diabetes.