HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver
Bi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, Timothy Hla
Bi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, Timothy Hla
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Research Article Therapeutics Vascular biology

HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver

Abstract

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 (S1P1) 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 S1P1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P1 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 S1P1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.

Authors

Bi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, Timothy Hla

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Figure 9

Effect of S1P1 agonist SEW2871 on liver regeneration and fibrosis in Apom-/- mice.

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Effect of S1P1 agonist SEW2871 on liver regeneration and fibrosis in Apo...
(A–C) Mouse survival rate (A), recovery of liver weight (B), and restoration of hepatic function (C) were tested in Apom-/- mice after oral gavage of S1P1 agonist SEW2871 or vehicle after PH. Plasma bilirubin level was measured to examine the functional recovery of liver mass. N = 6-8 mice per group. 10 mg/kg/day SEW2871 was administered via oral gavage for seven days immediately after BDL and another seven days between day 14 and day 21. P < 0.05 between vehicle and SEW2871 treated groups in B and C. Statistical difference was determined by One way ANOVA. (D–F) Sinusoidal vascular structure and platelet cell deposition in hepatectomized ApoM-/- mice treated with SEW2871. Vascular perfusion and platelet distribution in the liver were determined by staining of LSEC marker VEGFR3, i.v. injected B4-isolectin (D and E), and platelet marker CD41 (F). Immunostaining image is shown in (D), and perfused LSEC number was measured by quantification of VEGFR3+Isolectin+ area percentage (E). SEW2871 improved the perfusion of VEGFR3+ LSEC in Apom-/- mice. Note that S1P1 agonist treatment also reduced platelet cell number in the liver of Apom-/- mice (Supplemental Figure 3E), suggesting the alleviated thrombosis. N = 5 mice per group. Scale bar = 50 μm. (G and H) SEW2871 reduced maladaptive vascular remodeling and associated fibrosis in Apom-/- mouse liver after BDL. Vascular morphology alteration in treated Apom-/- mice was assessed by electron microscopy (G), and collagen deposition was measured by Sirius red staining (H). BDL disrupted the sinusoidal vasculature structure in Apom/- mice, and SEW2871 attenuated this maladaptive vascular remodeling, resulting in a sinusoidal structure displaying unperturbed cell junction (arrow) and endothelial morphology. Scale bar = 5 μm (G), 50 μm (H). (I) HDL-bound S1P and pharmacological agonist specific for S1P1 modulates liver regeneration. Perturbation of this pro-regenerative endothelial S1P1 pathway prohibits sinusoidal vascular regeneration and evokes a maladaptive vascular remodeling instigating fibrosis and thrombosis.