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Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.

dc.contributor.author Michelotti, Gregory A
dc.contributor.author Tucker, Anikia
dc.contributor.author Swiderska-Syn, Marzena
dc.contributor.author Machado, Mariana Verdelho
dc.contributor.author Choi, Steve S
dc.contributor.author Kruger, Leandi
dc.contributor.author Soderblom, Erik
dc.contributor.author Thompson, J Will
dc.contributor.author Mayer-Salman, Meredith
dc.contributor.author Himburg, Heather A
dc.contributor.author Moylan, Cynthia A
dc.contributor.author Guy, Cynthia D
dc.contributor.author Garman, Katherine S
dc.contributor.author Premont, Richard T
dc.contributor.author Chute, John P
dc.contributor.author Diehl, Anna Mae
dc.coverage.spatial England
dc.date.accessioned 2016-12-01T21:51:32Z
dc.date.issued 2016-04
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/25596181
dc.identifier gutjnl-2014-308176
dc.identifier.uri https://hdl.handle.net/10161/13095
dc.description.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. DESIGN: 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.
dc.language eng
dc.publisher BMJ
dc.relation.ispartof Gut
dc.relation.isversionof 10.1136/gutjnl-2014-308176
dc.subject CELL MIGRATION
dc.subject CHOLESTATIC LIVER DISEASES
dc.subject FIBROSIS
dc.subject IMMUNOHISTOCHEMISTRY
dc.subject STEM CELLS
dc.subject Animals
dc.subject Bile Ducts
dc.subject Biomarkers
dc.subject Blotting, Western
dc.subject Carrier Proteins
dc.subject Cell Differentiation
dc.subject Cell Movement
dc.subject Cytokines
dc.subject Immunohistochemistry
dc.subject Liver Diseases
dc.subject Mice
dc.subject Mice, Knockout
dc.subject Phosphoproteins
dc.subject RNA
dc.subject Real-Time Polymerase Chain Reaction
dc.subject Receptor-Like Protein Tyrosine Phosphatases, Class 5
dc.subject Signal Transduction
dc.title Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.
dc.type Journal article
duke.contributor.id Michelotti, Gregory A|0213796
duke.contributor.id Choi, Steve S|0278358
duke.contributor.id Soderblom, Erik|0488121
duke.contributor.id Thompson, J Will|0439139
duke.contributor.id Moylan, Cynthia A|0280057
duke.contributor.id Guy, Cynthia D|0211349
duke.contributor.id Premont, Richard T|0095901
duke.contributor.id Diehl, Anna Mae|0314922
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/25596181
pubs.begin-page 683
pubs.end-page 692
pubs.issue 4
pubs.organisational-group Basic Science Departments
pubs.organisational-group Cell Biology
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Faculty
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Gastroenterology
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pathology
pubs.organisational-group Pharmacology & Cancer Biology
pubs.organisational-group School of Medicine
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published
pubs.volume 65
dc.identifier.eissn 1468-3288
duke.contributor.orcid Choi, Steve S|0000-0001-9228-4060
duke.contributor.orcid Moylan, Cynthia A|0000-0001-8454-7086
duke.contributor.orcid Premont, Richard T|0000-0002-8053-5026


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