Peripheral-dominant liver fibrosis and tumor distribution in a mouse model of congestive hepatopathy.

AIM
Congestive hepatopathy often leads to liver fibrosis and hepatocellular carcinoma. Imaging modalities provided clinical evidence that elevation of liver stiffness and tumor occurrence are mainly induced in liver periphery of patients with congestive hepatopathy. However, clinical relevance of liver stiffness and liver fibrosis is unclear because liver congestion itself increases liver stiffness in congestive hepatopathy. It also unclear which factors configure such regional disparity of tumor development in patients with congestive hepatopathy. To answer these questions, we evaluated the macroscopic spatial distribution of liver fibrosis and tumors in murine model of congestive hepatopathy.


METHODS
Chronic liver congestion was induced by partial ligation of the suprahepatic inferior vena cava (pIVCL). Distribution of liver congestion, fibrosis, and tumors in pIVCL mice was assessed by histological findings, laser microdissection (LMD)-based qPCR and enhanced computed tomography. LMD-based RNA-seq was performed to identify causal factors which promotes tumor development in congestive hepatopathy.


RESULTS
Liver fibrosis was mainly induced in liver periphery and co-localized with distribution of liver congestion. Liver tumors were also induced in liver periphery where liver congestion and fibrosis occurred. LMD-based RNA-seq revealed the upregulation of extracellular matrix/collagen fibril related-, wound healing related-, angiogenesis related-, morphogenesis related-, and cell motility-related signaling pathways in liver periphery compared to liver center.


CONCLUSIONS
Our findings showed experimental relevance of liver congestion, fibrosis and tumor development in congestive hepatopathy, and may provide important locational information. Macroscopic regional disparity observed in this murine model should be considered to manage patients with congestive hepatopathy. This article is protected by copyright. All rights reserved.