Galectin-3 regulates hepatic progenitor cell expansion during liver injury.
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.


METHODS
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.
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Wei-Chen
WC
Hsieh
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Alison C
AC
Mackinnon
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Wei-Yu
WY
Lu
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Jonathan
J
Jung
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Luke
L
Boulter
MRC/Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Neil C
NC
Henderson
Department of Hepatology, Edinburgh Royal Infirmary, Edinburgh, UK.
Kenneth J
KJ
Simpson
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Baukje
B
Schotanus
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Davina
D
Wojtacha
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Tom G
TG
Bird
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Claire N
CN
Medine
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
David C
DC
Hay
Department of Respiratory Medicine and Allergy, Kings College Denmark Hill Campus, London, UK.
Tariq
T
Sethi
Department of Hepatology, Edinburgh Royal Infirmary, Edinburgh, UK.
John P
JP
Iredale
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Stuart J
SJ
Forbes
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004032:Diet / Q000009:adverse effects; D037502:Galectin 3 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055153:Stem Cell Niche / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D015854:Up-Regulation
D037502:Galectin 3; D007797:Laminin