title: Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3.
abstract: Regulatory proteins have been identified in embryonic development of the endocrine pancreas. It is unknown whether these factors can also play a role in the formation of pancreatic endocrine cells from postnatal nonendocrine cells. The present study demonstrates that adult human pancreatic duct cells can be converted into insulin-expressing cells after ectopic, adenovirus-mediated expression of the class B basic helix-loop-helix factor neurogenin 3 (ngn3), which is a critical factor in embryogenesis of the mouse endocrine pancreas. Infection with adenovirus ngn3 (Adngn3) induced gene and/or protein expression of NeuroD/beta2, Pax4, Nkx2.2, Pax6, and Nkx6.1, all known to be essential for beta-cell differentiation in mouse embryos. Expression of ngn3 in adult human duct cells induced Notch ligands Dll1 and Dll4 and neuroendocrine- and beta-cell-specific markers: it increased the percentage of synaptophysin- and insulin-positive cells 15-fold in ngn3-infected versus control cells. Infection with NeuroD/beta2 (a downstream target of ngn3) induced similar effects. These data indicate that the Delta-Notch pathway, which controls embryonic development of the mouse endocrine pancreas, can also operate in adult human duct cells driving them to a neuroendocrine phenotype with the formation of insulin-expressing cells.
authors.affiliation: Diabetes Research Center, Brussels Free University (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Heremans
authors.forename: Mark
authors.initials: M
authors.lastname: Van De Casteele
authors.forename: Peter
authors.initials: P
authors.lastname: in't Veld
authors.forename: Gerard
authors.initials: G
authors.lastname: Gradwohl
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
authors.forename: Ole
authors.initials: O
authors.lastname: Madsen
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
mesh_terms: D000328:Adult; D000367:Age Factors; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010183:Pancreatic Ducts / Q000166:cytology* / Q000196:embryology / Q000502:physiology*; D010641:Phenotype; D051880:Receptors, Notch; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; C498695:NEUROG3 protein, human; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; C064045:delta protein