Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells

J Biol Chem. 2020 Dec 4;295(49):16852-16862. doi: 10.1074/jbc.RA120.012974. Epub 2020 Sep 28.


Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.

Keywords: AMP-activated kinase (AMPK); Cell senescence; cell cycle; cellular senescence; galectin; galectin-3; glycoprotein; liver injury; proliferation; protein interaction; protein-protein interaction; quiescence; stem cells; stemness exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / chemistry
  • AC133 Antigen / metabolism
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Cephalosporins / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p16 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Dexamethasone / pharmacology*
  • Focal Adhesion Kinase 1 / metabolism
  • Galectin 3 / antagonists & inhibitors
  • Galectin 3 / genetics
  • Galectin 3 / metabolism*
  • Glycopeptides / pharmacology
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Stem Cell Niche / drug effects*
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Up-Regulation / drug effects*


  • AC133 Antigen
  • Cephalosporins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Galectin 3
  • Glycopeptides
  • RNA, Small Interfering
  • TD 1792
  • Dexamethasone
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse
  • AMP-Activated Protein Kinases