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PDGF-BB is involved in HIF-1α/CXCR4/CXCR7 axis promoting capillarization of hepatic sinusoidal endothelial cells

Jing Fang1,2, Qiang Ji1,2, Siqi Gao3

  • 1Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Heliyon
|January 23, 2023
PubMed

Insights

The HIF-1α/CXCR4/PDGF-BB/CXCR7 pathway drives liver fibrosis by promoting liver sinusoidal endothelial cell dedifferentiation and activating hepatic stellate cells. Targeting this axis may offer new therapeutic strategies for liver fibrosis.

Area of Science:

  • Hepatology and Fibrosis Research
  • Cell Biology
  • Molecular Mechanisms of Liver Disease

Background:

  • Liver sinusoidal endothelial cell (LSEC) capillarization, linked to the HIF-1α/CXCR4 pathway, promotes hepatic fibrosis.
  • The precise interaction between CXCR4 and CXCR7 in this process and the role of PDGF-BB remain unclear.

Purpose of the Study:

  • To investigate the role of PDGF-BB in LSEC dedifferentiation and hepatic stellate cell (HSC) activation.
  • To elucidate the mechanism connecting CXCR4 and CXCR7 in liver fibrosis.

Main Methods:

  • Analysis of HIF-1α/CXCR4 pathway activation in CCl4- and BDL-induced liver fibrosis models.
  • In vitro studies using inhibitors and lentiviral vectors to assess the effects of HIF-1α, CXCR4, and PDGF-BB on LSECs.
  • Co-culture experiments to demonstrate the interaction between LSECs and HSCs.

Main Results:

  • CXCR4 upregulation and CXCR7 downregulation correlated with LSEC capillarization and HSC activation in fibrotic livers.
  • HIF-1α and CXCR4 downregulation reduced LSEC dedifferentiation markers and increased CXCR7 expression.
  • PDGF-BB inhibition (using STI571) decreased PDGFR-β and increased CXCR7, inhibiting LSEC dedifferentiation and subsequent HSC activation.

Conclusions:

  • The HIF-1α/CXCR4/PDGF-BB/CXCR7 axis is a key driver of LSEC dedifferentiation.
  • This dedifferentiation process subsequently activates HSCs, promoting liver fibrosis.
  • Targeting this axis presents a potential therapeutic strategy for liver fibrosis.
Abstract

Keywords:
DedifferentiationHIF-1α/CXCR4 pathwayHepatic stellate cellsLiver sinusoidal endothelial cellsPDGF-BB

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