Cluster of Differentiation 44 Promotes Liver Fibrosis and Serves as a Biomarker in Congestive Hepatopathy

Abstract

Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium-binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH. (Hepatology Communications 2021;0:1-11).

Sphingosine‐1‐phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy

“…However, it is not proven to date that the same sequence is applicable for the progression of congestive liver disease. As we showed in this study and reported previously, [ 41 ] lesser degree of inflammation is obvious in the occurrence of fibrosis and tumor in this model. The possibility of distinct usage of S1PR subtypes involved in fibrosis or tumorigenesis, as we showed in this study, should raise concerns for the need of specification of molecular pathways in this entity of disease.…”

EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress

“…To achieve this concentration, we treated HA-administered mice with 10 mg/kg of Hermes-1 or isotype-matched immunoglobulin (IgG2a) twice a week. 38 As anticipated, the anti-CD44 antibody significantly reduced the number of EMD lesions per mouse from 1.38 ± 0.74 to 0.50 ± 0.76 ( P = .02191) ( Figure 3 F-G; supplemental Figure 4 B).

Figure 3.

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“…Beginning 4 weeks after transplantation, mice were administered 10 mg/kg of isotype-matched immunoglobulin (IgG) or the anti-CD44 antibody Hermes-1 (Anti-CD44) along with 50 μg/kg HA twice a week for an additional 4 weeks. 38 Representative overlay photographs taken by the IVIS-CT Imaging System on Day 70 are shown with the location of the intramedullary tumors, splenic tumors, and EMD lesions. (G) The numbers of EMD lesions in each mouse were counted.…”

CD44 expression in the bile duct epithelium is related to hepatic fibrosis in nonalcoholic steatohepatitis rats induced by a choline-deficient, methionine-lowered, L-amino acid diet

“…Hyaluronic acid is a member of the extracellular matrix and is deposited in the fibrotic liver 14 . Serum hyaluronic acid is one of the markers of severe hepatic fibrosis and cirrhosis 15 , and in the liver, CD44 is expressed in hepatic stellate cells which are closely related to hepatic fibrosis 16 . In severe lung fibrosis, CD44 regulates the invasive phenotype of fibroblasts through hyaluronic acid 17 .…”