AUTHOR=Guo Qianqian , Furuta Kunimaro , Islam Shahidul , Caporarello Nunzia , Kostallari Enis , Dielis Kobe , Tschumperlin Daniel J. , Hirsova Petra , Ibrahim Samar H. 

TITLE=Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver fibrosis

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.983255

DOI=10.3389/fimmu.2022.983255

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis.</p></sec><sec><title>Methods</title><p>Wild-type C57BL/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (<italic>Vcam1<sup>Δend</sup></italic>) and control mice (<italic>Vcam1<sup>fl/fl</sup></italic>) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from <italic>Vcam1<sup>fl/fl</sup></italic> or <italic>Vcam1<sup>Δend</sup></italic> and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a μ-Slide 2 well co-culture system.</p></sec><sec><title>Results</title><p>Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in <italic>Vcam1<sup>fl/fl</sup></italic> mice and restored in <italic>Vcam1<sup>Δend</sup></italic> mice in both NASH and liver fibrosis models. Co-immunostaining showed increased α-smooth muscle actin in the livers of <italic>Vcam1<sup>fl/fl</sup></italic> mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the <italic>Vcam1<sup>fl/fl</sup></italic> mice but not <italic>Vcam1<sup>Δend</sup></italic> mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed <italic>Vcam1<sup>Δend</sup></italic> mice compared to <italic>Vcam1<sup>fl/fl</sup></italic> mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs <italic>in vitro</italic>, supporting the profibrogenic role of LSEC VCAM1.</p></sec><sec><title>Conclusion</title><p>VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.</p></sec>