title: Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.
abstract: OBJECTIVE
  Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined.
  
  
  METHODS
  Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors.
  
  
  RESULTS
  We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells.
  
  
  CONCLUSIONS
  Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cavelti-Weder
authors.affiliation: Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Life Sciences and Technology, Shanghai, The People's Republic of China.|Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA.
authors.forename: Weida
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Zumsteg
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Stemann-Andersen
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA.
authors.forename: Yuemei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Lu
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Jermendy
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Yong Mong
authors.initials: YM
authors.lastname: Bee
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard University, Boston, MA, USA.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Sherman Fairchild 258C, 7 Divinity Ave, Cambridge, MA, 02138, USA. qiao_zhou@harvard.edu.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000502:physiology*; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology*; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000503:physiopathology*
keywords: Diabetes; Exocrine to beta cell reprogramming; Hyperglycaemia