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Insights into translational utility of rodent models of hepatic fibrosis
Author(s) -
Saravanan Chandrassegar,
Judge Joyce,
Song Yanli,
Dietrich Bill,
Wu Jing,
Bauer Andreas,
Mansfield Keith
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.924.14
Subject(s) - hepatic stellate cell , hepatic fibrosis , fibrosis , pathology , cirrhosis , immunostaining , biology , rodent , phenotype , ccl4 , carbon tetrachloride , medicine , immunohistochemistry , chemistry , gene , ecology , biochemistry , organic chemistry
Activation of hepatic stellate cells (HSCs) has been established as the dominant process in the progression of hepatic fibrosis. A number of phenotypic alterations occur during activation of HSCs, including proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis and retinoid loss. These phenotypic changes could serve as potential targets for anti‐fibrotic therapy. In the past, several rodent models have been used to delineate the mechanism of fibrogenesis. However, the translatability of these animal models for clinical development remains largely questionable. The goal of this study is to compare the number of proliferating HSCs in commonly used mouse models of hepatic fibrosis [carbon tetrachloride (CCl4), bile duct ligation (BDL) and metabolic disease (ob/ob high fat diet)] and human cirrhotic liver samples. Dual immunostaining for Ki67 (proliferative marker) and a marker for activated HSCs (aHSCs) on formalin fixed paraffin embedded liver sections were performed. Whole slide quantitative image analysis on dually immunostained human cirrhotic liver samples (n=5) showed only 1.9% (range 1.3–3%) of aHSCs cells were positive for Ki67. In contrast, BDL, ob/ob high fat diet, and CCl4 mouse models showed approximately 4%, 5%, and 17% of aHSCs were positive for Ki67, respectively. In summary, cognizance of the discrepancy in the number of proliferating HSCs between human cirrhotic samples and mouse models of fibrosis will assist in careful design of preclinical studies.