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

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

England

2016-12-01T21:51:32Z

2016-04

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.

http://www.ncbi.nlm.nih.gov/pubmed/25596181

gutjnl-2014-308176

1468-3288

https://hdl.handle.net/10161/13095

eng

BMJ

Gut

10.1136/gutjnl-2014-308176

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

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

Journal article

Choi, Steve S|0000-0001-9228-4060

Moylan, Cynthia A|0000-0001-8454-7086

Premont, Richard T|0000-0002-8053-5026

http://www.ncbi.nlm.nih.gov/pubmed/25596181

683

692

4

Basic Science Departments

Cell Biology

Clinical Science Departments

Duke

Duke Cancer Institute

Duke Institute for Brain Sciences

Faculty

Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Medicine, Gastroenterology

Molecular Genetics and Microbiology

Pathology

Pharmacology & Cancer Biology

School of Medicine

University Institutes and Centers

Published

65