Hepatic Hyperplasia Associated with Discordant Xenogeneic Parenchymal-Nonparenchymal Interactions in Human Hepatocyte-Repopulated Mice

Utoh, Rie; Tateno, Chise; Kataoka, Mikiko; Tachibana, Asato; Masumoto, Norio; Yamasaki, Chihiro; Shimada, Takashi; Itamoto, Toshiyuki; Asahara, Toshimasa; Yoshizato, Katsutoshi

doi:10.2353/ajpath.2010.090430

Cited by 23 publications

(19 citation statements)

References 37 publications

(41 reference statements)

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“…47 We have shown that humanized liver mice have aberrant liver-intestine bile acid signaling, a phenomenon which is likely present in all such models. For example, human hepatocyte repopulated uPA transgenic mice had livers 3 times the size of livers repopulated by rat hepatocytes, 23 but bile acids/signaling were not measured in this study. We anticipate that genetic correction (transgenic human FGF19) of bile acid signaling in this model will further extend its applicability to human diseases, especially relevant given the recent connection of Non-Alcoholic Fatty Liver Disease (NAFDL) to bile acid homeostasis and FGF19 signaling.…”

Section: Discussionmentioning

confidence: 79%

“…We have previously noted that FRG and FRGN mice transplanted with human hepatocytes have large livers, roughly three times the expected size, similar to human chimeric livers in uPA/SCID mice. 23 When Fah + mouse donor hepatocytes were used to repopulate the liver, there was no difference in liver size between FRGN and FRGN19+ mice, and the repopulated livers were the expected size (~5% of body weight) (Fig. 2d).…”

Section: Resultsmentioning

confidence: 89%

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Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers

Naugler¹,

Tarlow

Fedorov

et al. 2015

Gastroenterology

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Background & Aims The ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize fibroblast growth factor-15 (FGF15) produced by mouse intestine. This results in upregulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool. We investigated whether abnormal bile acid signaling affects the hepatostat in mice. Methods We crossed Fah−/−, Rag2−/−, Il2r−/− mice with NOD mice to create FRGN mice, whose livers can be fully repopulated with human hepatocytes. We inserted the gene for human FGF19 (ortholog to mouse Fgf15), including regulatory sequences, into the FRGN mice to create FRGN19+ mice. Livers of FRGN19+ mice and their FRGN littermates were fully repopulated with human hepatocytes. Liver tissues were collected and bile acid pool sizes and RNA sequences were analyzed and compared with those of mice without humanized livers (controls). Results Livers were larger in FRGN mice with humanized livers (13% of body weight), compared to control FRGN mice; they also had much larger bile acid pools and aberrant bile acid signaling. Livers from FRGN19+ normalized to 7.8% of body weight, and their bile acid pool and signaling more closely resembled that of control FRGN19+ mice. RNA sequence analysis showed activation of the Hippo pathway, and immunohistochemical and transcription analyses revealed increased hepatocyte proliferation, but not apoptosis, in the enlarged humanized livers of FRGN mice. Cell sorting experiments showed that although healthy human liver does not produce FGF19, non-parenchymal cells from cholestatic livers produce FGF19. Conclusions In mice with humanized livers, expression of an FGF19 transgene corrects bile acid signaling defects, resulting in normalization of bile acid synthesis, the bile acid pool, and liver size. These findings indicate that liver size is, in part, regulated by the size of the bile acid pool that the liver must circulate.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 89%

Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers

Naugler¹,

Tarlow

Fedorov

et al. 2015

Gastroenterology

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show abstract

“…In addition, a simple low tyrosine diet can be used as NTBC replacement 9,10 . The biochemical and histological characterization of repopulated uPA-transgenics and Fah knockouts has been well described 5,11 . Importantly, repopulated livers in both systems display normal function and morphology of human hepatocytes.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Mice With Human Livers

2013

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“…Frozen sections were prepared from the livers of five h-GHtreated and 36 chimeric h-GH-untreated mice 6YF and stained with Oil Red O (ORO). When necessary, serial sections were stained with anti-h-CK8/18 antibodies (MP Biomedicals, Aurora, OH) that did not react with m-hepatocytes as previously described (19). Steatosis grading of h-hepatocytes was performed on ORO-stained chimeric mouse liver sections as follows: grade 0, no lipid droplets; grade 1, appearance of small lipid droplets; grade 2, small and middle-sized lipid droplets; grade 3, small to large droplets (Fig.…”

Section: Immunohistochemistry Lipid Staining and Grading Of Steatosmentioning

confidence: 99%

Growth Hormone-Dependent Pathogenesis of Human Hepatic Steatosis in a Novel Mouse Model Bearing a Human Hepatocyte-Repopulated Liver

Tateno

Kataoka²,

Utoh³

et al. 2011

Endocrinology

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Clinical studies have shown a close association between nonalcoholic fatty liver disease and adult-onset GH deficiency, but the relevant molecular mechanisms are still unclear. No mouse model has been suitable to study the etiological relationship of human nonalcoholic fatty liver disease and human adult-onset GH deficiency under conditions similar to the human liver in vivo. We generated human (h-)hepatocyte chimeric mice with livers that were predominantly repopulated with h-hepatocytes in a h-GH-deficient state. The chimeric mouse liver was mostly repopulated with h-hepatocytes about 50 d after transplantation and spontaneously became fatty in the h-hepatocyte regions after about 70 d. Infusion of the chimeric mouse with h-GH drastically decreased steatosis, showing the direct cause of h-GH deficiency in the generation of hepatic steatosis. Using microarray profiles aided by real-time quantitative RT-PCR, comparison between h-hepatocytes from h-GH-untreated and -treated mice identified 14 GH-up-regulated and four GH-down-regulated genes, including IGF-I, SOCS2, NNMT, IGFLS, P4AH1, SLC16A1, SRD5A1, FADS1, and AKR1B10, respectively. These GH-up- and -down-regulated genes were expressed in the chimeric mouse liver at lower and higher levels than in human livers, respectively. Treatment of the chimeric mice with h-GH ameliorated their altered expression. h-Hepatocytes were separated from chimeric mouse livers for testing in vitro effects of h-GH or h-IGF-I on gene expression, and results showed that GH directly regulated the expression of IGF-I, SOCS2, NNMT, IGFALS, P4AH1, FADS1, and AKR1B10. In conclusion, the chimeric mouse is a novel h-GH-deficient animal model for studying in vivo h-GH-dependent human liver dysfunctions.

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Hepatic Hyperplasia Associated with Discordant Xenogeneic Parenchymal-Nonparenchymal Interactions in Human Hepatocyte-Repopulated Mice

Cited by 23 publications

References 37 publications

Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers

Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers

Mice With Human Livers

Growth Hormone-Dependent Pathogenesis of Human Hepatic Steatosis in a Novel Mouse Model Bearing a Human Hepatocyte-Repopulated Liver

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