title: 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 S1P1in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P1enhanced 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 S1P1to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.
authors.affiliation: 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.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.|Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Swendeman
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Bongnam
authors.initials: B
authors.lastname: Jung
authors.affiliation: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Deebly
authors.initials: D
authors.lastname: Chavez
authors.affiliation: 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.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.|Department of Biomedical Sciences.
authors.forename: Christina
authors.initials: C
authors.lastname: Christoffersen
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.|Department of Biomedical Sciences.|Department of Clinical Medicine, University of Copenhagen, Denmark.
authors.forename: Lars Bo
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Department of Pathology, Skirball Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Schwab
authors.affiliation: Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.|Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla