title: TNF-like weak inducer of apoptosis (TWEAK) promotes beta cell neogenesis from pancreatic ductal epithelium in adult mice.
abstract: OBJECTIVE
  The adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis) promotes β-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice.
  
  
  METHODS
  C57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreER(TM): R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14) deficient mice after Px.
  
  
  RESULTS
  TWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic α- or β-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic β-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion.
  
  
  CONCLUSIONS
  We conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.
authors.affiliation: Department of Immunobiology, Biogen Idec, Cambridge, Massachusetts, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.forename: Aniela
authors.initials: A
authors.lastname: Jakubowski
authors.forename: Lihe
authors.initials: L
authors.lastname: Su
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000074049:Cytokine TWEAK; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000502:physiology / Q000601:surgery; D010180:Pancreatectomy; D010183:Pancreatic Ducts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074050:TWEAK Receptor; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000074049:Cytokine TWEAK; D007633:Keratins; D009419:Nerve Tissue Proteins; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; C407737:Neurog3 protein, mouse; C000613297:TNFRSF12A protein, human; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse