Journal
JCI INSIGHT
Volume 1, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.87058
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Funding
- National Heart, Lung, and Blood Institute [R01HL089934, R37 HL067330, R01HL130826, R01HL097797, R01HL119872]
- Ansary Stem Cell Institute, National Scientist Development Grant from the American Heart Association [12SDG1213004]
- Key National Research and Development Program focused on Stem Cell and Translational Research [2016YFA0101600]
- Ministry of Science and Technology, China
- Empire State Stem Cell Board and New York State Department of Health [C024180, C026438, C026878, C028117]
- Novonordisk foundation [NNF13OC0003898]
- National Institute of Health [R01AI085166]
- Novo Nordisk Fonden [NNF13OC0003898] Funding Source: researchfish
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Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P 1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this maladaptive repair phenotype was recapitulated in mice that lack S1P 1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P 1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P 1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.
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