title: Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas.
abstract: OBJECTIVE
  Animal studies have indicated that pancreatic exocrine acinar cells have phenotypic plasticity. In rodents, acinar cells can differentiate into ductal precursors that can be converted to pancreatic ductal adenocarcinoma or insulin-producing endocrine cells. However, little is known about human acinar cell plasticity. We developed nongenetic and genetic lineage tracing methods to study the fate of human acinar cells in culture.
  
  
  METHODS
  Human exocrine tissue was obtained from organ donors, dissociated, and cultured. Cell proliferation and survival were measured, and cell phenotypes were analyzed by immunocytochemistry. Nongenetic tracing methods were developed based on selective binding and uptake by acinar cells of a labeled lectin (Ulex europaeus agglutinin 1). Genetic tracing methods were developed based on adenoviral introduction of a Cre-lox reporter system, controlled by the amylase promoter.
  
  
  RESULTS
  Both tracing methods showed that human acinar cells can transdifferentiate into cells that express specific ductal markers, such as cytokeratin 19, hepatocyte nuclear factor 1β, SOX9, CD133, carbonic anhydrase II, and cystic fibrosis transmembrane conductance regulator. Within 1 week of culture, all surviving acinar cells had acquired a ductal phenotype. This transdifferentiation was decreased by inhibiting mitogen-activated protein kinase signaling.
  
  
  CONCLUSIONS
  Human acinar cells have plasticity similar to that described in rodent cells. These results might be used to develop therapeutic strategies for patients with diabetes or pancreatic cancer.
authors.affiliation: Cell Differentiation Laboratory, Diabetes Research Center, Free University of Brussels, Brussels, Belgium. ihoubrac@vub.ac.be
authors.forename: Isabelle
authors.initials: I
authors.lastname: Houbracken
authors.forename: Evelien
authors.initials: E
authors.lastname: de Waele
authors.forename: Jessy
authors.initials: J
authors.lastname: Lardon
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ling
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
authors.forename: Luc
authors.initials: L
authors.lastname: Bouwens
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D054338:Cell Transdifferentiation / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D017930:Genes, Reporter; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D037121:Plant Lectins / Q000493:pharmacokinetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D015415:Biomarkers; D006023:Glycoproteins; D053539:Keratin-19; D019394:Ki-67 Antigen; C000606023:PROM1 protein, human; D010455:Peptides; D037121:Plant Lectins; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; C036850:Ulex europaeus lectins; C485184:enhanced green fluorescent protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051539:Hepatocyte Nuclear Factor 1-beta; D049452:Green Fluorescent Proteins; D020928:Mitogen-Activated Protein Kinases; D002918:Chymotrypsin; D024402:Carbonic Anhydrase II