Insulin expressing cells that have been differentiated from human pluripotent stem cells in vitro lack the glucose responsiveness characteristic of mature β-cells. β-cell maturation in mice was studied to find genetic markers that enable screens for factors that induce bona fide β-cells in vitro. We find that functional β-cell maturation is marked by an increase in the glucose threshold for insulin secretion and by expression of the gene urocortin 3.

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The pancreas develops from two separate and independent endodermal primordia. The molecular events supporting the early morphological changes that give rise to the formation of the dorsal and ventral pancreatic buds result from coordinated responses to extrinsic and intrinsic signals. The extrinsic signals are involved in processes dictating whether progenitor cells remain as immature or as committed precursors. After specification, the sequential activation of transcription factors determines cell autonomously the commitment and differentiation of these progenitors. During pancreas development, the roles of extrinsic and intrinsic signals are variable, depending on the particular competence of each progenitor cell. We summarize in this review the main events, at the level of gene expression, which are involved in the early stages of pancreas development. KEY WORDS: islet, pancreas, progenitor, endocrine, development, beta cell The pancreas is an exocrine and endocrine gland of the digestive system (Fig. 1A). The exocrine part represents 95-99% of the total pancreatic mass. It consists of serous acini of highly polarized cells that produce digestive enzymes (amylase, lipase, phospholipase) as well as pro-enzymes (elastase, procarboxypeptidase, trypsinogen, pepsinogen, deoxyribonuclease, ribonuclease), which are stored in zymogen granules located in their apical pole (Fig. 1CD). Once secreted with water and bicarbonates into the lumen of the acinus, they become activated and forwarded through the ductal network to the duodenum, for the intestinal digestion of nutrients. The ductal tree begins within the acini with very small ducts lined by centroacinar cells, followed by intercalated, intralobular and finally interlobular ducts (Fig. 1CD).The endocrine pancreas is composed of islets of Langerhans scattered within the exocrine tissue, representing 1-5% of the pancreatic mass (Fig. 1BC). Adult islets are composed of different cell types characterized by the production of specific hormones: glucagon by α-cells, insulin by β-cells, somatostatin by δ-cells and pancreatic polypeptide by PP-cells. A rare fifth endocrine cell type, the ε-cell, secreting ghrelin, represents about 1% of the embryonic endocrine pancreas, but disappears after birth. In rodents, islets are composed of a central core of β-cells, which represent about 80% of all islet cells, surrounded by a mantle composed of the three other cell types (Fig. 1E). Insulin and glucagon control blood glucose levels, whereas PP and ghrelin are orexigenic hormones and somatostatin regulates the secretion of insulin, glucagon and PP.Int. J. Dev. Biol. 52: 823-835 (2008) doi: 10.1387/ijdb.072444cb Specification of pancreatic fateIn Mammals, the pancreatic differentiation program is induced in the foregut/midgut junction of the endoderm by factors released from the mesoderm at the 6-10 somites stage (6-10s) (Fig. 2). Initially, the dorsal endoderm is adjacent to the notochord, before the fusion of the two dorsal aortae at 12-20s (which corresponds to E8...