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- Title
Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver fibrosis.
- Authors
Qianqian Guo; Kunimaro Furuta; Islam, Shahidul; Caporarello, Nunzia; Kostallari, Enis; Dielis, Kobe; Tschumperlin, Daniel J.; Hirsova, Petra; Ibrahim, Samar H.
- Abstract
Background: 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. Methods: 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 cellspecific Vcam1 deleted mice (Vcam1Dend) and control mice (Vcam1fl/fl) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from Vcam1fl/fl or Vcam1Dend and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a m-Slide 2 well co-culture system. Results: Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in Vcam1fl/fl mice and restored in Vcam1Dend mice in both NASH and liver fibrosis models. Co-immunostaining showed increased a-smooth muscle actin in the livers of Vcam1fl/fl mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the Vcam1fl/fl mice but not Vcam1Dend mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CDHFD fed Vcam1Dend mice compared to Vcam1fl/fl mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs in vitro, supporting the profibrogenic role of LSEC VCAM1. Conclusion: VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.
- Subjects
HEPATIC fibrosis; CELL adhesion molecules; VASCULAR cell adhesion molecule-1; VASCULAR endothelial cells; YAP signaling proteins; LIVER cells
- Publication
Frontiers in Immunology, 2022, Vol 13, p1
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2022.983255