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Galectin-3 regulates hepatic progenitor cell expansion during liver injury
  1. Wei-Chen Hsieh1,
  2. Alison C Mackinnon1,
  3. Wei-Yu Lu1,
  4. Jonathan Jung1,
  5. Luke Boulter1,
  6. Neil C Henderson2,
  7. Kenneth J Simpson3,
  8. Baukje Schotanus1,
  9. Davina Wojtacha1,
  10. Tom G Bird1,
  11. Claire N Medine1,
  12. David C Hay1,
  13. Tariq Sethi4,
  14. John P Iredale3,
  15. Stuart J Forbes1
  1. 1MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
  2. 2MRC/Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
  3. 3Department of Hepatology, Edinburgh Royal Infirmary, Edinburgh, UK
  4. 4Department of Respiratory Medicine and Allergy, Kings College Denmark Hill Campus, London, UK
  1. Correspondence to Professor Stuart J Forbes, MRC Centre for Regenerative Medicine, SCRM Building, University of Edinburgh, Edinburgh Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, UK; stuart.forbes{at}ed.ac.uk

Abstract

Objective Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.

Design We examined the role of Gal-3 in HPC activation. HPC activation was studied following dietary induced hepatocellular (choline-deficient ethionine-supplemented diet) and biliary (3,5-diethoxycarbonyl-1,4-dihydrocollidine supplemented diet) injury in wild type and Gal-3(−/−) mice.

Results HPC proliferation was significantly reduced in Gal-3(−/−) mice. Gal-3(−/−) mice failed to form a HPC niche, with reduced laminin formation. HPCs isolated from wild type mice secrete Gal-3 which enhanced adhesion and proliferation of HPCs on laminin in an undifferentiated form. These effects were attenuated in Gal3(−/−) HPCs and in wild type HPCs treated with the Gal-3 inhibitor lactose. Gal-3(−/−) HPCs in vitro showed increased hepatocyte function and prematurely upregulated both biliary and hepatocyte differentiation markers and regulated cell cycle genes leading to arrest in G0/G1.

Conclusions We conclude that Gal-3 is required for the undifferentiated expansion of HPCs in their niche in injured liver.

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