Glucose upregulates a limited number of genes in human beta cells.

ABSTRACT: Although a large set of data is available concerning organogenesis in animal models, information remains scarce on human organogenesis. In this work, we performed temporal mapping of human fetal pancreatic organogenesis using cell surface markers. We demonstrate that in the human fetal pancreas at 7 weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate either into the acinar, ductal and endocrine lineages. Development towards the acinar lineage is paralleled by a substantial increase in GP2 expression. Conversely, a subset of the multipotent GP2+ population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3, an early marker of endocrine differentiation. Endocrine maturation will progress by up-regulating SUSD2 and lowering ECAD levels. Finally, we show that in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work constitutes a powerful approach to more precisely define intermediate cell population during conversion of multipotent progenitors into the 3 main human pancreatic cell types (acinar, ductal and endocrine) in vivo. As such, the data pave the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated. While the mechanisms by which glucose regulates insulin secretion from pancreatic beta cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralogue ChREBP, is the predominant glucose-responsive transcription factor in human pancreatic beta EndoC-βH1 cells and in human islets. In high glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes ARRDC4 and TXNIP, the latter being a protein strongly linked to beta-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human beta cells, using forskolin or the GLP-1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that modulating MondoA expression functionally affects glucose uptake. These results highlight MondoA as a novel target in beta cells that coordinates transcriptional response to elevated glucose levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98501 | GEO | 2017/05/04

SECONDARY ACCESSION(S): PRJNA385303

REPOSITORIES: GEO