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Pleiotrophin Regulates the Ductular Reaction by Controlling the Migration

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Gut Online First, published on March 10, 2015 as 10.1136/gutjnl-2014-308176 Hepatology ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2014-308176 on 16 January 2015. Downloaded from Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches Gregory A Michelotti,1 Anikia Tucker,1 Marzena Swiderska-Syn,1 Mariana Verdelho Machado,1 Steve S Choi,1,2 Leandi Kruger,1 Erik Soderblom,3 J Will Thompson,3 Meredith Mayer-Salman,3 Heather A Himburg,4 Cynthia A Moylan,1,2 Cynthia D Guy,5 Katherine S Garman,1,2 Richard T Premont,1 John P Chute,4 Anna Mae Diehl1 ▸ Additional material is ABSTRACT published online only. To view Objective The ductular reaction (DR) involves Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ mobilisation of reactive-appearing duct-like cells (RDC) gutjnl-2014-308176). along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space 1Division of Gastroenterology, What is already known about this subject? Duke University, Durham, of Disse. Perivascular cells in stem cell niches produce ▸ Various types of liver injury promote a ductular North Carolina, USA pleiotrophin (PTN) to inactivate the PTN receptor, protein reaction (DR) characterised by the periportal 2Section of Gastroenterology, tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby accumulation of small ductules, myofibroblasts Durham Veterans Affairs augmenting phosphoprotein-dependent signalling. We and collagen matrix. Medical Center, Durham, ▸ Pleiotrophin (PTN) is a heparin-binding growth North Carolina, USA hypothesised that the DR is regulated by PTN/PTPRZ1 3Proteomics Center, signalling. factor that inhibits constitutive tyrosine Duke University, Durham, Design PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and phosphatase activity of its receptor, protein North Carolina, USA tyrosine phosphatase receptor Z1 (PTPRZ1) to 4 wild type (WT) mice were examined before and after bile Division of Hematology and duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC regulate fate decisions in various stem/progenitor Oncology, UCLA, Los Angeles, and HSC from WT, PTN-KO, and PTPRZ1-KO mice were cells. California, USA ▸ In the liver, PTN expression is induced in several 5 also treated with PTN to determine effects on Department of Pathology, conditions associated with liver progenitor Duke University, Durham, downstream signaling phosphoproteins, gene expression, accumulation, including bile duct ligation, partial North Carolina, USA http://gut.bmj.com/ growth, and migration. Liver biopsies from patients with hepatectomy and hepatocellular carcinoma. Correspondence to DRs were also interrogated. ▸ Liver regeneration is inhibited in PTN-deficient Professor Anna Mae Diehl, Results Although quiescent HSC and RDC lines mice after partial hepatectomy, suggesting that Division of Gastroenterology, expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTN promotes liver repair. Duke University, Durham, PTPRZ1 protein was demonstrated in healthy liver. BDL NC 27710, USA; induced PTN in MF-HSC and increased PTPRZ1 in MF- What are the new findings? [email protected] HSC and RDC. In WT mice, BDL triggered a DR ▸ Cells in putative liver stem/progenitor niches, that is, GAM and AT contributed characterised by periportal accumulation of collagen, the space of Disse and canals of Hering, express on September 26, 2021 by guest. Protected copyright. equally. RDC and MF-HSC. All aspects of this DR were increased PTN and its receptor, PTPRZ1 and modulate in PTN-KO mice and suppressed in PTPRZ1-KO mice. In PTN/PTPRZ1 expression during liver injury. Received 1 August 2014 ▸ vitro studies revealed PTN-dependent accumulation of PTN-PTPRZ1 signalling controls the mobilisation Revised 19 December 2014 of cells that normally reside in stem/progenitor phosphoproteins that control cell-cell adhesion and Accepted 22 December 2014 niches of adult livers, thereby regulating the migration, with resultant inhibition of cell migration. intensity of the DR. PTPRZ1-positive cells were prominent in the DRs of ▸ PTN-PTPRZ1 interaction in liver cells modulates patients with ductal plate defects and adult cholestatic the tyrosine phosphorylation of factors that diseases. control cell-cell adhesion, cell-matrix interactions Conclusions PTN, and its receptor, PTPRZ1, regulate and cell migration. the DR to liver injury by controlling the migration of ▸ PTPRZ1 is prominent in the DRs of von resident cells in adult liver progenitor niches. Meyenburg complexes, adult polycystic liver disease, primary biliary cirrhosis and primary sclerosing cholangitis. How might it impact on clinical practice in INTRODUCTION the foreseeable future? Various types of liver injury promote a ductular ▸ PTN/PTPRZ1 signalling might be manipulated reaction (DR) characterised by the periportal accu- To cite: Michelotti GA, therapeutically to optimise recovery from chronic mulation of small ductules comprised of cholestatic liver injury. Tucker A, Swiderska-Syn M, fi et al. Gut Published Online reactive-appearing duct-like cells (RDC), myo bro- ▸ Inter-individual differences in PTN/PTPRZ1 First: [please include Day blasts (MF) and collagen matrix. Neither the pathway activity might be exploited as Month Year] doi:10.1136/ mechanisms driving this DR, nor its biological sig- biomarkers for progressive liver fibrosis. gutjnl-2014-308176 nificance, are well understood.1 Bipotent liver Michelotti GA, et al. Gut 2015;0:1–10. doi:10.1136/gutjnl-2014-308176 1 Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Hepatology progenitors that can differentiate into ductular cells reside along MATERIALS AND METHODS canals of Hering; vestiges of fetal ductal plates that persist Human liver biopsies Gut: first published as 10.1136/gutjnl-2014-308176 on 16 January 2015. Downloaded from around portal tracts in adult livers.2 Multipotent liver progeni- Anonomised unstained liver sections from formalin-fixed paraf- tors have also been identified in submucosal glands within the fin embedded tissue blocks of individuals with normal liver (3), wall of the adult biliary tree.3 Mature hepatocyte and cholangio- adult polycystic disease (n=1), von Meyenburg complexes cytes can also cause RDC with properties of liver progenitors.45 (n=1), primary biliary cirrhosis (n=2) and primary sclerosing It has been suggested that the DR reflects injury-related mobil- cholangitis (n=4) were obtained from the Duke Department of isation of liver progenitors from varying sources.6 We evaluated Pathology in accordance with our Duke IRB-approved protocol. the hypothesis that the DR is regulated by pleiotrophin (PTN) Liver sections were processed for immunohistochemistry as and its receptor, protein tyrosine phosphatase receptor zeta-1 detailed below. (PTPRZ1). PTN regulates fate decisions in various stem/progenitor Mice 7–12 cells. PTN expression has been demonstrated in two condi- PTN-GFP, PTN knockout (KO), and PTPRZ1 KO mice have tions associated with accumulation of liver progenitors; partial been previously described.11 C57BL/6 and SV129 brown WT 13–16 hepatectomy (PH) and hepatocellular carcinoma (HCC). mice were used as strain-specific controls for PTN KO and Bile duct ligation (BDL), a well-established stimulus for the DR, PTPRZ1-KO mice, respectively, and were obtained from The 17 also induces PTN. PTN appears to promote liver growth Jackson Laboratory and Taconic, respectively. because regeneration after PH is inhibited in PTN-deficient To induce cholestatic injury, adult (10–12 weeks) mice (C57BL/ 14 mice. PTN is known to interact with various molecules, 6 WT (n=7), PTN-KO (n=9) mice, SV129 brown WT (n=6), and including syndecans, integrins, anaplastic lymphoma kinase PTPRZ1-KO mice (n=8)) underwent BDL or sham surgery (n=3/ (ALK) and PTPRZ1. Among these, PTPRZ1 is best charac- group). After 14 days, animals were euthanised; blood and tissues terised as a true receptor for PTN because PTN-PTPRZ1 inter- were obtained as described.28 All studies were performed in action inhibits the constitutive tyrosine phosphatase activity of accordance with a Duke University IACUC-approved protocol. PTPRZ1, resulting in accumulation of phosphorylated tyrosine residues in ALK and other proteins that are ordinarily depho- 18 19 Cell culture sphorylated by PTPRZ1. Prolonged PTN-dependent Primary cell isolation from mice phospho-tyrosine-mediated tyrosine kinase activity modulates 920 Primary HSC, LSEC, and hepatocytes were isolated from a signalling in an array of kinase cascades, such as PI3-kinase, 28 30 821 21 12-week-old mice. Akt, extracellular-signal regulated kinase (ERK)1/2, and HSC and LSEC viability and purity were greater than 95% as α β 22 PKC / , providing a mechanism by which PTN might globally previously described,28 30 HSCs were cultured for up to 9 days impact cell fate. Cytoskeletal proteins that regulate migration, in standard Dulbecco’s Modified Eagle Medium supplemented proliferation, and differentiation, are downstream effectors 23–25 with 10% fetal bovine serum, and 1% penicillin-streptomycin. regulated by PTPRZ1. Hepatocytes were used immediately for RNA isolation. Cell In certain stem cell niches, PTN is expressed by endothelial 11 viability exceeded 90% in all experiments as determined by cells. Although resident liver pericytes (a.k.a., hepatic stellate Trypan-blue exclusion. http://gut.bmj.com/ cells (HSC)) produce PTN, it is not known if liver sinusoidal The murine ductular
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