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

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Date
2016-04
Authors
Michelotti, Gregory A
Tucker, Anikia
Swiderska-Syn, Marzena
Machado, Mariana Verdelho
Choi, Steve S
Kruger, Leandi
Soderblom, Erik
Thompson, J Will
Mayer-Salman, Meredith
Himburg, Heather A
Moylan, Cynthia A
Guy, Cynthia D
Garman, Katherine S
Premont, Richard T
Chute, John P
Diehl, Anna Mae
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(16 total)
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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.
Type
Journal article
Subject
CELL MIGRATION
CHOLESTATIC LIVER DISEASES
FIBROSIS
IMMUNOHISTOCHEMISTRY
STEM CELLS
Animals
Bile Ducts
Biomarkers
Blotting, Western
Carrier Proteins
Cell Differentiation
Cell Movement
Cytokines
Immunohistochemistry
Liver Diseases
Mice
Mice, Knockout
Phosphoproteins
RNA
Real-Time Polymerase Chain Reaction
Receptor-Like Protein Tyrosine Phosphatases, Class 5
Signal Transduction
Permalink
https://hdl.handle.net/10161/13095
Published Version (Please cite this version)
10.1136/gutjnl-2014-308176
Publication Info
Michelotti, Gregory A; Tucker, Anikia; Swiderska-Syn, Marzena; Machado, Mariana Verdelho; Choi, Steve S; Kruger, Leandi; ... Diehl, Anna Mae (2016). Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches. Gut, 65(4). pp. 683-692. 10.1136/gutjnl-2014-308176. Retrieved from https://hdl.handle.net/10161/13095.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Choi

Steven Sok Choi

Associate Professor of Medicine
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
Diehl

Anna Mae Diehl

Florence McAlister Distinguished Professor of Medicine
Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholi
Guy

Cynthia Dianne Guy

Professor of Pathology
My research interests include: Fine Needle Aspiration of Liver, Gastrointestinal Tract, and Pancreatic Lesions Biliary Duct Brushings Nonalcoholic Fatty Liver Disease/NASH Liver Fibrogenesis

Gregory Alexander Michelotti

Associate Professor in Medicine
The goal of my research is to elucidate mechanisms underlying catecholamine-induced myocardial hypertrophy and identify unique pathways directing adaptive (physiologic) versus maladaptive (pathologic) responses. Stimulation of α1aAR has been shown to mediate myocardial hypertrophy, culminating in both morphological and genetic cellular changes, however it is unknown if α1ARs simply trigger initial hypertrophic events or rather preferentially activate adaptive
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Moylan

Cynthia Ann Moylan

Associate Professor of Medicine
My research interests focus on the study of chronic liver disease and primary liver cancer, particularly from nonalcoholic fatty liver disease (NAFLD).  As part of the NAFLD Research Team at Duke, I am investigating the role of epigenetics and genetics on the development of advanced fibrosis from NAFLD.  The long term goal of our research is to develop non-invasive biomarkers to identify those patients at increased risk for cirrhosis and end stage liver disease in order to risk stratif
Premont

Richard Thomas Premont

Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular signals from neurotransmitters and hormones acting on cell surface receptors. Receptors transduce these signals to alter intracellular metabolism and cellular responsiveness through heterotrimeric G protein/second messenger pathways or through small GTP-binding protein/protein kinase cascades. The mechanisms that control the responsiveness of target organ G protein-coupled receptors include receptor ph

Erik James Soderblom

Assistant Research Professor of Cell Biology
Thompson

J. Will Thompson

Adjunct Assistant Professor in the Department of Pharmacology & Cancer Biology
Dr. Thompson's research focuses on the development and deployment of proteomics and metabolomics mass spectrometry techniques for the analysis of biological systems. He served as the Assistant Director of the Proteomics and Metabolomics Shared Resource in the Duke School of Medicine from 2007-2021. He currently maintains collaborations in metabolomics and proteomics research at Duke, and develops new tools for chemical analysis as a Princi
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