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Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches
  1. Gregory A Michelotti1,
  2. Anikia Tucker1,
  3. Marzena Swiderska-Syn1,
  4. Mariana Verdelho Machado1,
  5. Steve S Choi1,2,
  6. Leandi Kruger1,
  7. Erik Soderblom3,
  8. J Will Thompson3,
  9. Meredith Mayer-Salman3,
  10. Heather A Himburg4,
  11. Cynthia A Moylan1,2,
  12. Cynthia D Guy5,
  13. Katherine S Garman1,2,
  14. Richard T Premont1,
  15. John P Chute4,
  16. Anna Mae Diehl1
  1. 1Division of Gastroenterology, Duke University, Durham, North Carolina, USA
  2. 2Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA
  3. 3Proteomics Center, Duke University, Durham, North Carolina, USA
  4. 4Division of Hematology and Oncology, UCLA, Los Angeles, California, USA
  5. 5Department of Pathology, Duke University, Durham, North Carolina, USA
  1. Correspondence to Professor Anna Mae Diehl, Division of Gastroenterology, Duke University, Durham, NC 27710, USA; annamae.diehl{at}dm.duke.edu

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.

  • CELL MIGRATION
  • FIBROSIS
  • CHOLESTATIC LIVER DISEASES
  • IMMUNOHISTOCHEMISTRY
  • STEM CELLS

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