Ding Bi-Sen, Liu Catherine H, Sun Yue, Chen Yutian, Swendeman Steven L, Jung Bongnam, Chavez Deebly, Cao Zhongwei, Christoffersen Christina, Nielsen Lars Bo, Schwab Susan R, Rafii Shahin, Hla Timothy
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
JCI Insight. 2016 Dec 22;1(21):e87058. doi: 10.1172/jci.insight.87058.
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) 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 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P 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 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.
肝窦状血管系统的再生对于无纤维化的肝脏再生及其代谢能力的恢复至关重要。然而，关于这种特殊的血管微环境是如何再生的，我们知之甚少。在这里，我们表明，高密度脂蛋白（HDL）结合的天然配体激活内皮鞘氨醇-1-磷酸受体-1（S1P）（HDL-S1P）可诱导肝脏再生并减少纤维化。在缺乏HDL-S1P的小鼠中，部分肝切除术后的肝脏再生受到阻碍，并与异常的血管重塑、血栓形成和窦周纤维化有关。值得注意的是，在内皮细胞中缺乏S1P的小鼠中也出现了这种“适应性不良修复”表型。相反，在小鼠慢性损伤和胆汁淤积模型中，HDL-S1P血浆水平升高或给予SEW2871（一种对S1P具有特异性的药理激动剂）可增强代谢功能血管的再生并减轻纤维化。这项研究表明，天然和药理配体可调节内皮S1P以刺激肝脏再生并抑制纤维化，这表明激活该途径可能是治疗肝纤维化的一种新策略。
