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NTPDase3 antibody targets adult human pancreatic β-cells for in vitro and in vivo analysis

ABSTRACT: Identification of cell surface markers specific to human pancreatic β-cells would allow in vivo analysis and imaging. Here we introduce a biomarker – ectonucleoside triphosphate diphosphohydrolase-3 (NTPDase3) – that is expressed on the cell surface of essentially all adult human β-cells, including those from individuals with type 1 or type 2 diabetes (T1D, T2D). NTPDase3 is expressed dynamically during postnatal human pancreas development, appearing first in acinar cells at birth, but several months later its expression declines in acinar cells while concurrently emerges in islet β-cells. Given its specificity and membrane localization, we utilized an NTPDase3 antibody for purification of live human β-cells as confirmed by transcriptional profiling, and, in addition, for in vivo imaging of transplanted human β-cells. Thus, NTPDase3 is a cell surface biomarker of adult human β-cells and the antibody directed to this protein should be a useful new reagent for β-cell sorting, in vivo imaging, and targeting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116559 | GEO | 2018/09/12

REPOSITORIES: GEO

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Project description: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.

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NTPDase3 antibody targets adult human pancreatic β-cells for in vitro and in vivo analysis

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