A New Mdr2−/− Mouse Model of Sclerosing Cholangitis with Rapid Fibrosis Progression, Early-Onset Portal Hypertension, and Liver Cancer

Ikenaga, Naoki; Liu, Susan B.; Sverdlov, Deanna Y.; Yoshida, Shuhei; Nasser, Imad; Ke, Qingen; Kang, Peter M.; Popov, Yury

doi:10.1016/j.ajpath.2014.10.013

Cited by 81 publications

(80 citation statements)

References 38 publications

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“…Progenitor cell origins of liver cancer, at least for a subset of tumors, have been suggested for both hepatocellular carcinoma and cholangiocarcinoma based on histopathological observations and global gene expression analysis . Mdr2 −/− mice develop cirrhosis and multiple primary liver cancers (hepatocellular carcinoma) with 100% penetrance, beginning at 10 months of age . To assess the effect of impaired progenitor responses in the absence of αvβ6 on the development of liver cancer, we evaluated tumor incidence and burden in aged Mdr2 −/− ;Itgb6 −/− and Mdr2 −/− mice (12 mice of each genotype).…”

Section: Resultsmentioning

confidence: 99%

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

et al. 2015

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Integrin αvβ6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFβ1). In human liver cirrhosis, αvβ6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvβ6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvβ6-dependent TGFβ1 activation. Freshly isolated αvβ6+ liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by αvβ6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-αvβ6 antibody is recapitulated by TGFβ1 neutralization and rescued by addition of bioactive TGFβ1. Genetic disruption or selective targeting of αvβ6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. Conclusion These results suggest that αvβ6 is a promising target for chronic fibrotic liver diseases and associated cancers.

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Section: Resultsmentioning

confidence: 99%

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

et al. 2015

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“…Rapid reoccurrence of fibrosis has been described in patients that undergo liver transplantation for hepatic fibrosis or cirrhosis (4). Rapid lung fibrosis could be induced by inhalative toxins in animal models (5, 6), and rapid liver fibrosis is seen in some models of primary sclerosing cholangitis (7). These data and further evidence support the concept that under certain circumstances fibrosis and subsequent stricture formation in some CD patients may be much faster than traditionally assumed.…”

Section: Introductionmentioning

confidence: 99%

Factors Promoting Development of Fibrosis in Crohn’s Disease

Rogler

Hausmann

2017

Front. Med.

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The concepts on the pathophysiology of intestinal fibrosis in Crohn’s disease (CD) have changed in recent years. Some years ago fibrosis was regarded to be a consequence of long-standing inflammation with subsequent destruction of the gut wall matrix followed by scar formation and collagen deposition. Fibrosis in CD patients appeared to be an irreversible process that could hardly be influenced. Therefore, the main target in CD therapy was to control inflammation to avoid fibrosis development. Many of these assumptions seem to be only partially true. Inflammation may be a necessary prerequisite for the initiation of fibrosis. However, when the pathophysiologic processes that lead to fibrosis in CD patients have been initiated fibrosis development may be independent of inflammation and may continue even when inflammation is under good medical control. Fibrosis in CD also may be reversible. After strictureplasty local collagen deposits decrease or even disappear. With new animal models for intestinal fibrosis on the horizon, we need to spend more efforts on understanding the factors influencing fibrosis in CD patients to finally find specific therapies. In this context, it will be as important to find markers and quantitative imaging tools to have reliable endpoints for clinical trials in fibrosing CD.

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“…The multidrug resistance protein 2 (Mdr2) (Abcb4) knockout mouse is an established preclinical model of fibrosing cholangiopathy, whereby absence of the phospholipid floppase Mdr2 at the hepatocyte canalicular membrane results in “toxic” low phospholipid bile, precipitation of unopposed biliary bile acid and cholesterol, and subsequent sterile inflammation driving bile duct epithelial injury and rapidly progressive biliary fibrosis . The mice develop sclerosing cholangitis (SC) with cholestasis, bile duct proliferation, and bridging fibrosis . In this model, there is altered expression and cellular localization of canalicular transporters early in the disease course, microcrystal formation in bile ducts, bile leak, and disruption of basement membranes with subsequent sterile inflammation and neutrophil‐recruitment to sites of injury .…”

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Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis

et al. 2018

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In the multidrug resistance protein 2 (Mdr2) mouse model, low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2 mice, intrahepatic CD8+ lymphocytes were expanded, and contraction of intrahepatic Tregs coincided with rising serum alanine transferase and alkaline phosphatase (ALP) levels between days 14-30 of life. Antibody-mediated depletion of intrahepatic CD8+ lymphocytes during that time reduced ALP levels and the expression of osteopontin (Opn), a pro-fibrogenic cytokine. Depletion of intrahepatic Tregs with anti-CD25 antibody between days 7-30 increased intrahepatic CD8+ T cells, Opn expression, and fibrosis. Conversely, expansion of intrahepatic Tregs with interleukin 2/anti-interleukin 2 immune complexes (IL-2c) downregulated hepatic expression of Opn and Tnf, reduced frequency of intrahepatic CD8+ lymphocytes, and diminished biliary injury and fibrosis. Treatment with IL-2c upregulated hepatic Treg expression of CD39, an ectonucleotidase capable of hydrolyzing pro-inflammatory adenosine triphosphate. In vitro, Tregs expressing CD39 suppressed the proliferation of hepatic CD8+ lymphocytes from Mdr2 mice more efficiently than those lacking CD39. In infants with BA, infiltration of interlobular bile ducts with CD8+ cells was associated with biliary expression of Opn and its transcription was negatively correlated with mRNA expression of Treg-associated genes. Conclusion: Hepatic CD8+ T lymphocytes drive biliary injury and fibrosis in murine SC. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL-2c, suggesting that Treg-directed low-dose Il-2 treatment may be considered as therapy for SC.

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A New Mdr2−/− Mouse Model of Sclerosing Cholangitis with Rapid Fibrosis Progression, Early-Onset Portal Hypertension, and Liver Cancer

Cited by 81 publications

References 38 publications

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

Factors Promoting Development of Fibrosis in Crohn’s Disease

Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis

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