Glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis through activation of TGF-β- and PDGF-like signals in hepatic stellate cells

  • Sci Rep. 2017 Sep 8;7(1):11006. doi: 10.1038/s41598-017-11212-1.
Ming-Heng Wu  1  2 ,  Yuh-Ling Chen  3 ,  Kuen-Haur Lee  4 ,  Che-Chang Chang  5 ,  Tsai-Mu Cheng  5 ,  Szu-Yuan Wu  6  7 ,  Chao-Chiang Tu  8 ,  Wan-Lin Tsui  5
Affiliations
  • 1. Graduate Institute of Translational Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 2. Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 3. Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 4. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan.
  • 5. Graduate Institute of Translational Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan.
  • 6. Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 7. Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 8. Department of General Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
PMID: 28887481 DOI: 10.1038/s41598-017-11212-1
Abstract

Concomitant expressions of glycan-binding proteins and their bound glycans regulate many pathophysiologic processes, but this issue has not been addressed in liver fibrosis. Activation of hepatic stellate cells (HSCs) is a rate-limiting step in liver fibrosis and is an important target for liver fibrosis therapy. We previously reported that Galectin (Gal)-1, a β-galactoside-binding protein, regulates myofibroblast homeostasis in oral carcinoma and wound healing, but the role of Gal-1 in HSC migration and activation is unclear. Herein, we report that Gal-1 and its bound glycans were highly expressed in fibrotic livers and activated HSCs. The cell-surface glycome of activated HSCs facilitated Gal-1 binding, which upon recognition of the N-glycans on neuropilin (NRP)-1, activated platelet-derived growth factor (PDGF)- and transforming growth factor (TGF)-β-like signals to promote HSC migration and activation. In addition, blocking endogenous Gal-1 expression suppressed PDGF- and TGF-β1-induced signaling, migration, and gene expression in HSCs. Methionine and choline-deficient diet (MCD)-induced Collagen deposition and HSC activation were attenuated in Gal-1-null mice compared to wild-type mice. In summary, we concluded that glycosylation-dependent Gal-1/NRP-1 interactions activate TGF-β and PDGF-like signaling to promote the migration and activation of HSCs. Therefore, targeting Gal-1/NRP-1 interactions could be developed into liver fibrosis therapy.

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