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.

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Citation

Published Version (Please cite this version)

10.1136/gutjnl-2014-308176

Publication Info

Michelotti, Gregory A, Anikia Tucker, Marzena Swiderska-Syn, Mariana Verdelho Machado, Steve S Choi, Leandi Kruger, Erik Soderblom, J Will Thompson, et al. (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.

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Scholars@Duke

Choi

Steven Sok Choi

Associate Professor of Medicine

Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration

Soderblom

Erik James Soderblom

Associate Research Professor of Cell Biology

Director, Proteomics and Metabolomics Core Facility

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


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