title: Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.
abstract: OBJECTIVE
  The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling.
  
  
  METHODS
  PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated.
  
  
  RESULTS
  Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases.
  
  
  CONCLUSIONS
  PTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches.
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Anikia
authors.initials: A
authors.lastname: Tucker
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Mariana Verdelho
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
authors.forename: Steve S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Leandi
authors.initials: L
authors.lastname: Kruger
authors.affiliation: Proteomics Center, Duke University, Durham, North Carolina, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Soderblom
authors.affiliation: Proteomics Center, Duke University, Durham, North Carolina, USA.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: Proteomics Center, Duke University, Durham, North Carolina, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Mayer-Salman
authors.affiliation: Division of Hematology and Oncology, UCLA, Los Angeles, California, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Himburg
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Moylan
authors.affiliation: Department of Pathology, Duke University, Durham, North Carolina, USA.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Guy
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Garman
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: Division of Hematology and Oncology, UCLA, Los Angeles, California, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Chute
authors.affiliation: Division of Gastroenterology, Duke University, Durham, North Carolina, USA.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D012313:RNA / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D016207:Cytokines; D010750:Phosphoproteins; C066845:pleiotrophin; D012313:RNA; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: CELL MIGRATION; CHOLESTATIC LIVER DISEASES; FIBROSIS; IMMUNOHISTOCHEMISTRY; STEM CELLS