Faculty Collaboration Database

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches. Gut 2016 Apr;65(4):683-92

Date

01/18/2015

Pubmed ID

25596181

Pubmed Central ID

PMC4504836

DOI

10.1136/gutjnl-2014-308176

Scopus ID

2-s2.0-84929919170 (requires institutional sign-in at Scopus site)   25 Citations

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.

Author List

Michelotti GA, Tucker A, Swiderska-Syn M, Machado MV, Choi SS, Kruger L, Soderblom E, Thompson JW, Mayer-Salman M, Himburg HA, Moylan CA, Guy CD, Garman KS, Premont RT, Chute JP, Diehl AM

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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