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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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

Thompson

J. Will Thompson

Adjunct Assistant Professor in the Department of Pharmacology and 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 Principal Scientist at 908 Devices in Carrboro, NC.

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 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 interested in understanding risks for progressive liver disease including developmental programming and in utero exposures and have been investigating these risks through studies of the Newborn Epigenetics Study (NEST).  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 stratify patients as well as to develop better preventative and therapeutic strategies.

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

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 nonalcoholic fatty liver disease (NAFLD).

Research by our group has advanced understanding in two main areas: 1) immune system regulation of liver injury and regeneration and 2)the role of fetal morphogens, such as the hedgehog pathway, in regulating fibrotic responses to liver damage. Our basic research programs have been enjoyed continuous NIH support since 1989. We welcome students, post-doctoral fellows and visiting scientists who have interests in this research area to contact us about training opportunities and potential collaborations.

Since 2001 we have also been an active participant in the NIDDK-funded Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), a national consortium comprised of 8 university medical centers selected to generate a national registry for patients with NAFLD and to conduct multicenter treatment trials for this disorder. We are actively recruiting patients for this program, as well as a number of other industry-supported NAFLD studies.


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