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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. 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 articleSubject
CELL MIGRATIONCHOLESTATIC 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
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https://hdl.handle.net/10161/13095Published Version (Please cite this version)
10.1136/gutjnl-2014-308176Publication 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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Show full item recordScholars@Duke
Steven Sok Choi
Associate Professor of Medicine
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
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
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.
Cynthia Ann Moylan
Associate Professor of Medicine
My research interests focus on the study of chronic liver disease and primary liver
cancer, particularly from metabolic dysfunction associated steatotic liver disease
(MASLD), formerly called nonalcoholic fatty liver disease (NAFLD). As part of the
MASLD Research Team at Duke, we are investigating the role of environmental contaminants,
epigenetics, and genetics on the development of advanced fibrosis and liver cancer
from MASLD and other chronic liver diseases. We are also intereste
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
Associate Research Professor of Cell Biology
Director, Proteomics and Metabolomics Core Facility
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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