title: Plasticity of adult human pancreatic duct cells by neurogenin3-mediated reprogramming.
abstract: OBJECTIVE
  Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it.
  
  
  METHODS
  The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming.
  
  
  RESULTS
  Ngn3 stimulates duct cells to express a focused set of genes that are characteristic for islet endocrine cells and/or neural tissues. This neuro-endocrine shift however, is incomplete with less than 10% of full duct-to-endocrine reprogramming achieved. Transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1.
  
  
  CONCLUSIONS
  The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes.
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Swales
authors.forename: Geert A
authors.initials: GA
authors.lastname: Martens
authors.forename: Stefan
authors.initials: S
authors.lastname: Bonné
authors.forename: Yves
authors.initials: Y
authors.lastname: Heremans
authors.forename: Rehannah
authors.initials: R
authors.lastname: Borup
authors.forename: Mark
authors.initials: M
authors.lastname: Van de Casteele
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ling
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.forename: Finn
authors.initials: F
authors.lastname: Nielsen
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
mesh_terms: D000328:Adult; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D054338:Cell Transdifferentiation / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051473:Maf Transcription Factors, Large; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C485159:MAFA protein, human; C078341:MYT1 protein, human; C498695:NEUROG3 protein, human; C407737:Neurog3 protein, mouse; C064045:delta protein; C084010:pancreatic and duodenal homeobox 1 protein