GH enhances proliferation of human hepatocytes grafted into immunodeficient mice with damaged liver

Masumoto, Norio; Tateno, Chise; Tachibana, Asato; Utoh, Rie; Morikawa, Yoshio; Shimada, Takashi; Momisako, Hiroyuki; Itamoto, Toshiyuki; Asahara, Toshimasa; Yoshizato, Katsutoshi

doi:10.1677/joe-07-0126

Cited by 27 publications

(26 citation statements)

References 30 publications

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“…Recently, we showed that h-hepatocytes in h-hep-mice are growth hormone-deficient, because mouse growth hormone does not recognize the human growth hormone receptor of h-hepatocytes. 37 However, we consider that h-hepatocytes would be able to respond to TGF-␤ if the host m-HSCs secreted it, because there has been no report of species specificity between h-and m-TGF-␤. In the present study we clearly demonstrated the coincidence of lack of TGF-␤/TGFBR signaling with the hyperplasia of h-hepmouse liver.…”

Section: Discussionmentioning

confidence: 99%

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

Utoh

Tateno

Kataoka

et al. 2010

The American Journal of Pathology

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Liver mass is optimized in relation to body mass. Rat (r) and human (h) hepatocytes were transplanted into liver-injured immunodeficient mice and allowed to proliferate for 3 or 11 weeks, respectively, when the transplants stopped proliferating. Liver/body weight ratio was normal throughout in r-hepatocytebearing mice (r-hep-mice), but increased continuously in h-hepatocyte-bearing mice (h-hep-mice), until reaching approximately three times the normal m-liver size, which was considered to be hyperplasia of h-hepatocytes because there were no significant differences in cell size among host (mouse Experiments using animal models with damaged livers have demonstrated the high replicative potential of hepatocytes. A transgenic (Tg) mouse carrying an albumin (Alb) enhancer/promoter-driven murine urokinase-type plasminogen activator (uPA) gene was created 1 ; the liver of this mouse degenerates and increases hepatocyte growth factor production and induces the proliferation of normal hepatocytes.2 When transplanted into the uPA-Tg mice, mouse (m) hepatocytes engrafted into the host liver and proliferated, eventually replacing the host hepatocytes with a replacement index (RI) of 80%, 3 where RI represents the ratio of the regions occupied by transplanted hepatocytes in the host liver). The offspring generated by crossing uPA-Tg mice with immunodeficient mice were used as hosts for the xenotransplantation of rat (r), 4 woodchuck, 5 and human (h) hepatocytes. 6 -8 We showed that the repopulation kinetics of r-hepatocytes in uPA/severe combined immunodeficiency (SCID) mice were different from those of h-hepatocytes.9 Rat

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Section: Discussionmentioning

confidence: 99%

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

Utoh

Tateno

Kataoka

et al. 2010

The American Journal of Pathology

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“…Importantly, human hepatocytes in the livers of chimeric mice are susceptible to growth enhancing activities. The treatment of chimeric mice with human growth hormone (hGH) increases the repopulation speed and the replacement index of transplanted human hepatocytes, as determined by increased replicative DNA synthesis and the up-regulation of hGH-related signalling molecules (Masumoto et al, 2007). Furthermore, treatment with epidermal growth factor (Yamada et al, 2014) and partial hepatectomy (personal communication, Dr. Chise Tateno) also enhances hepatocellular proliferation in this chimeric mouse model.…”

Section: Epsilon-momfluorothrinmentioning

confidence: 98%

“…Information on the donors of the hepatocyte preparations used is presented in Table 1. Hepatocytes from these three donors were selected for transplantation because cells from young subjects are more responsive to the stimulation of hepatocellular proliferation (Masumoto et al, 2007). For the purposes of transplantation, vials of cryopreserved human hepatocytes (5-10 x 10 6 cells/vial) were thawed and transplanted into 20-60 cDNA-uPA/SCID mice (2.5 x 10 5 viable cells/ mouse).…”

Section: Chimeric Mouse Study Animalsmentioning

confidence: 99%

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

et al. 2017

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-High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 μM) and a major metabolite Z-CM-CA (5-1,000 μM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans.

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“…4 -6 ( Table 2)], three chimeric mice with hepatocytes 6YF [nos. 4 -6 ( Table 2)], one chimeric mouse 9MM (not included in Table 2), and one chimeric mouse 6YF (not included in Table 2) were continuously infused with 2.5 mg/kg⅐d h-GH (Wako, Osaka, Japan) through an sc-implanted Alzet micro-osmotic pump (Alza Corp., Palo Alto, CA) for 2 wk before killing (6,17). Blood h-albumin (Alb) and serum h-IGF-I in the mice were quantified as previously reported (6).…”

Section: Animals Transplantation Of H-hepatocytes and Treatment Of mentioning

confidence: 99%

“…However, we noticed that the mice spontaneously developed hepatic steatosis as the time after transplantation was prolonged. The h-hepatocytes of a chimeric mouse are in a GH-deficient state (6) primarily because human cells do not react with rodent GH (7), thus suggesting that the observed lipid accumulation in h-hepatocytes was caused by a lack of available h-GH in chimeric mice.…”

mentioning

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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GH enhances proliferation of human hepatocytes grafted into immunodeficient mice with damaged liver

Cited by 27 publications

References 30 publications

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

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

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

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

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