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OGAWA Tomohiro


FacultyDepartment of Biotechnology and Chemistry / General Education Division / Research Institute of Fundamental Technology for Next Generation
Commentator Guide
Last Updated :2020/09/30

Education and Career


  •  - 2002 , Hiroshima University, Graduate School, Division of Natural Science
  •  - 2000 , Hiroshima University, Faculty of Science
  •   1996 04  - 2000 03 , Hiroshima University, Faculty of Science
  •   2000 04  - 2002 03 , Hiroshima University, Graduate School of Science
  •   2002 04  - 2006 09 , Hiroshima University, Graduate School of Science

Academic & Professional Experience

  •   2014 04 ,  - 現在, Faculty of Engineering, Kindai University
  •   2016 09 ,  - 2017 08 , Department of Pathology, University of Southern California
  •   2011 04 ,  - 2014 03 , Faculty of Engineering, Kindai University
  •   2006 11 ,  - 2008 09 , Osaka City University
  •   2003 09 ,  - 2006 10 , Research Institute for Radiation Biology and Medicine, Hiroshima University

Research Activities

Research Areas

  • Life sciences, Gastroenterology
  • Life sciences, Molecular biology

Research Interests

  • Hepatology

Published Papers

  • Development of Capsular Fibrosis beneath the Liver Surface in Humans and Mice., Balog S, Li Y, Ogawa T, Miki T, Saito T, French SW, Asahina K, Hepatology (Baltimore, Md.), Hepatology (Baltimore, Md.), Jun. 2019 , Refereed
  • Isolation of a unique hepatic stellate cell population expressing integrin α8 from embryonic mouse livers, Tomohiro Ogawa, Yuchang Li, Ingrid Lua, Andrea Hartner, Kinji Asahina, Developmental Dynamics, Developmental Dynamics, 247(6), 867 - 881, Jun. 01 2018 , Refereed
    Summary:Background: Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. However, little is known about their phenotype and role in liver development. The aim of this study is to identify specific markers for embryonic HSCs. Results: Using antibodies against ALCAM and PDPN, we separated mesothelial cells (MCs) and HSCs from developing livers and identified integrin α8 (ITGA8) as a marker for embryonic desmin+ HSCs that are preferentially localized near the developing liver surface and α-smooth muscle actin+ perivascular mesenchymal cells around the vein. A cell lineage–tracing study revealed that upon differentiation, MC-derived HSCs or perivascular mesenchymal cells express ITGA8 during liver development. Using anti-ITGA8 antibodies, we succeeded in isolating MC-derived HSCs and perivascular mesenchymal cells from embryonic livers. In direct co-culture, ITGA8+ mesenchymal cells promoted the expression of hepatocyte and cholangiocyte markers in hepatoblasts. In the normal adult liver, expression of ITGA8 was restricted to portal fibroblasts in the portal triad. Upon liver injury, myofibroblasts increased the expression of ITGA8. Conclusions: ITGA8 is a specific cell surface marker of MC-derived HSCs and perivascular mesenchymal cells in the developing liver. Our data suggest that ITGA8+ mesenchymal cells maintain the phenotype of hepatoblast in liver development. Developmental Dynamics 247:867–881, 2018. © 2018 Wiley Periodicals, Inc.
  • Down-Regulation of Cyclin E1 Expression by MicroRNA-195 Accounts for Interferon-beta-Induced Inhibition of Hepatic Stellate Cell Proliferation, Yumiko Sekiya, Tomohiro Ogawa, Masashi Iizuka, Katsutoshi Yoshizato, Kazuo Ikeda, Norifumi Kawada, JOURNAL OF CELLULAR PHYSIOLOGY, JOURNAL OF CELLULAR PHYSIOLOGY, 226(10), 2535 - 2542, Oct. 2011
    Summary:Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA-195 (miR-195). We found that miR-195 was prominently down-regulated in the proliferative phase of primary-cultured mouse HSCs. Supporting this fact, IFN-beta induced miR-195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX-2. IFN-beta down-regulated cyclin E1 and up-regulated p21 mRNA levels in LX-2 cells. Luciferase reporter assay revealed the direct interaction of miR-195 with the cyclin E1 3'UTR. Overexpression of miR-195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX-2 cells. Moreover miR-195 inhibition restored cyclin E1 levels that were down-regulated by IFN-beta. In conclusion, IFN-beta inhibited the proliferation of LX-2 cells by delaying cell cycle progression in G1 to S phase, partially through the down-regulation of cyclin E1 and up-regulation of p21. IFN-induced miR-195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver. J. Cell. Physiol. 226: 2535-2542, 2011. (C) 2010 Wiley-Liss, Inc.
  • Changes in sequences of core region, interferon sensitivity-determining region and interferon and ribavirin resistance-determining region of hepatitis C virus genotype 1 during interferon-alpha and ribavirin therapy, and efficacy of retreatment, Ritsuzo Kozuka, Masaru Enomoto, Hoang Hai, Tomohiro Ogawa, Mika Nakaya, Atsushi Hagihara, Hideki Fujii, Sawako Kobayashi, Shuji Iwai, Hiroyasu Morikawa, Akihiro Tamori, Norifumi Kawada, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 42(12), 1157 - 1167, Dec. 2012
    Summary:Aim: Some regions associated with sensitivity to interferon-a and ribavirin have been identified in the hepatitis C virus (HCV) genome, including amino acid 70 in the core region (core a.a. 70), a.a. 22092248 (interferon sensitivity-determining region, ISDR) and a.a. 23342379 (interferon and ribavirin resistance-determining region, IRRDR). Methods: We examined changes in the sequences of these regions in 25 patients with chronic HCV genotype 1 infection who had not had sustained virological response (SVR) to interferon-a and ribavirin for 2448 weeks and subsequently received retreatment for 4872 weeks. Results: At baseline, the core a.a. 70 was mutant (resistant) type in seven patients. At the start of retreatment, the core a.a. 70 had changed from sensitive to resistant type in 2 patients, and SVR was not achieved by retreatment. The ISDR variations were resistant type (01 mutations) in 17 patients at baseline. After 2 weeks of treatment, amino acid change was found in two patients; in one, the substitutions returned to baseline status after treatment, and in the other, the substitution persisted. At the start of retreatment, ISDR sequences had changed from resistant to sensitive type in two patients and SVR was achieved and from sensitive to resistant type in three patients and SVR was not achieved. The IRRDR variations were resistant type (<6 mutations) in 19 patients at baseline and at the start of retreatment. Conclusion: Sequences of the core region and ISDR sometimes change during anti-HCV therapy, potentially affecting the outcomes of retreatment.
  • MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis, Tomohiro Ogawa, Masaru Enomoto, Hideki Fujii, Yumiko Sekiya, Katsutoshi Yoshizato, Kazuo Ikeda, Norifumi Kawada, GUT, GUT, 61(11), 1600 - 1609, Nov. 2012
    Summary:Background MicroRNAs (miRNAs) are important in hepatic pathophysiology and the development of liver cancer. Objective To explore miRNAs that are regulated with the progression of liver fibrosis caused by chronic liver disease. Design The regulated miRNAs in human livers infected with hepatitis C virus were identified by microarray analysis. Their expression in human livers with nonalcoholic steatohepatitis, mouse livers from two fibrosis models and cultured stellate cells was validated by realtime RT-PCR. The regulation of miR-222 expression in stellate cells by nuclear factor kappa B (NF-kappa B) was assayed. Finally, the effects of an miR-222 precursor or inhibitor on the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) and the growth of LX-2 cells were determined. Results It was found that miR-199a-5p/199a-3p and miR-221/222 were upregulated in the human liver in a fibrosis progressionedependent manner. Among these miRNAs, miR-221/222 were upregulated in LX-2 cells and increased during the course of culture-dependent activation of mouse primary stellate cells, in a manner similar to the expression of alpha 1(I) collagen and alpha-smooth muscle actin mRNAs. The expression of miR-221/222 increased in mouse models of liver fibrosis. In contrast, an NF-kappa B inhibitor significantly suppressed the miR-222 induction that was stimulated in culture by transforming growth factor alpha or tumour necrosis factor alpha. Although overexpression or downregulation of miR-222 failed to regulate the growth of LX-2 cells, miR-222 bound to the CDKN1B 3'UTR and regulated the expression of the corresponding protein. Conclusion miR-221/222 may be new markers for stellate cell activation and liver fibrosis progression.
  • Induction of microRNA-214-5p in human and rodent liver fibrosis, Masashi Iizuka, Tomohiro Ogawa, Masaru Enomoto, Hiroyuki Motoyama, Katsutoshi Yoshizato, Kazuo Ikeda, Norifumi Kawada, Fibrogenesis and Tissue Repair, Fibrogenesis and Tissue Repair, 5(1), 12, Aug. 01 2012
    Summary:Background: miRNAs are non-coding RNAs that regulate gene expression in a wide range of biological contexts, including a variety of diseases. The present study clarified the role of miR-214-5p in hepatic fibrogenesis using human clinical tissue samples, livers from rodent models, and cultured hepatic stellate cells.Methods: The expression of miR-214-5p and genes that are involved in liver fibrosis were analyzed in hepatitis C virus-infected human livers, rodent fibrotic livers, a human stellate cell line (LX-2), and the cells from intact mouse livers using real-time PCR. The effect of miR-214-5p overexpression in LX-2 cells on cell function was investigated. Twist-1 expression in the liver tissues of mouse models and primary-cultured stellate cells was also analyzed.Results: miR-214-5p was upregulated in human and mouse livers in a fibrosis progression-dependent manner. miR-214-5p expression increased during the culture-dependent activation of mouse primary stellate cells and was significantly higher in stellate cells than in hepatocytes. The overexpression of miR-214-5p in LX-2 cells increased the expression of fibrosis-related genes, such as matrix metalloproteinase (MMP)-2, MMP-9, α-smooth muscle actin, and transforming growth factor (TGF)-β1. TGF-β stimulation induced miR-214-5p in LX-2 cells. Twist-1 was increased in fibrotic mouse livers and induced during mouse stellate cell activation.Conclusion: miR-214-5p may play crucial roles in the activation of stellate cells and the progression of liver fibrosis. Twist-1 may regulate miR-214-5p expression in the liver, particularly in stellate cells. © 2012 Iizuka et al. licensee BioMed Central Ltd.
  • Close correlation of liver stiffness with collagen deposition and presence of myofibroblasts in non-alcoholic fatty liver disease, Mami Mori, Hideki Fujii, Tomohiro Ogawa, Sawako Kobayashi, Shuji Iwai, Hiroyasu Morikawa, Masaru Enomoto, Akihiro Tamori, Ayumi Sawada, Setsuko Takeda, Norifumi Kawada, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 41(9), 897 - 903, Sep. 2011
    Summary:Aim: Transient elastography is known as a rapid, objective, and highly reliable technique for staging hepatic fibrosis caused by hepatitis C virus infection; however, the relationship between degree of fibrosis and the collagen deposition or the accumulation of myofibroblasts in non-alcoholic fatty liver disease (NAFLD) remains to be further elucidated. Methods: The subjects were 36 patients with NAFLD who received liver biopsy and liver stiffness measurement using transient elastography. Their clinical data and laboratory values were collected. Morphometric analyses of liver fibrosis indicated by collagen deposition and the relative numbers of myofibroblasts were performed. Results: Liver stiffness measured by transient elastography correlated with histopathological fibrosis staging of NAFLD determined by Brunt's scoring system (P = 0.000149). The fibrosis staging correlated with the ratios of the Sirius redpositive area (P = 0.000032) and alpha-smooth muscle actin-positive area (P = 0.000898). Finally, liver stiffness significantly correlated with the ratios of the Sirius red-positive area (r = 0.390, P = 0.0184) and alpha-smooth muscle actin-positive area (r = 0.333, P = 0.0471). Conclusions: Liver stiffness measurement by transient elastography is valuable for evaluating fibrotic progression in NAFLD.
  • Promotion of Liver and Lung Tumorigenesis in DEN-Treated Cytoglobin-Deficient Mice, Le Thi Thanh Thuy, Takashi Morita, Kayo Yoshida, Kenichi Wakasa, Masashi Iizuka, Tomohiro Ogawa, Mami Mori, Yumiko Sekiya, Shinobu Momen, Hiroyuki Motoyama, Kazuo Ikeda, Katsutoshi Yoshizato, Norifumi Kawada, AMERICAN JOURNAL OF PATHOLOGY, AMERICAN JOURNAL OF PATHOLOGY, 179(2), 1050 - 1060, Aug. 2011
    Summary:Cytoglobin (Cygb) is a recently discovered vertebrate globin with molecular characteristics that are similar to myoglobin. To study the biological function of Cygb in vivo, we generated Cygb knockout mice and investigated their susceptibility to N,N-diethylnitrosamine (DEN)-induced tumorigenesis. Four-week-old male mice were administered DEN in drinking water at a dose of 25 ppm for 25 weeks or 0.05 ppm for 36 weeks. Cygb deficiency promoted the DEN-induced development of liver and lung tumors. All Cygb(+/-) and Cygb(-/-) mice treated with 25-ppm DEN exhibited liver tumors, compared with 44.4% of their wild-type counterparts. Lung tumors were present only in Cygb-deficient mice. More than 40% of Cygb(-/-) mice developed liver and lung tumors at the nontoxic dose of DEN (0.05 ppm), which did not induce tumors in wild-type mice. Cygb loss was associated with increased cancer cell proliferation, elevated extracellular signal-regulated kinase and Akt activation, overexpression of IL-1 beta, IL-6, Tnf alpha, and Tgf beta 3 mRNAs, and hepatic collagen accumulation. Cygb-deficient mice also exhibited increased nitrotyrosine formation and dysregulated expression of cancer-related genes (cyclin D2, p53, Pak1, Src, Cdkn2a, and Cebpa). These results suggest that Cygb deficiency induces susceptibility to cancer development in the liver and lungs of mice exposed to DEN. Thus, globins such as Cygb will shed new light on the biological features of organ carcinogenesis. (Am J Pathol 2011, 179:1050-1060; DOI: 10.1016/j.ajpath.2011.05.006)
  • Suppression of hepatic stellate cell activation by microRNA-29b, Yumiko Sekiya, Tomohiro Ogawa, Katsutoshi Yoshizato, Kazuo Ikeda, Norifumi Kawada, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 412(1), 74 - 79, Aug. 2011
    Summary:MicroRNAs (miRNAs) participate in the regulation of cellular functions including proliferation, apoptosis, and migration. It has been previously shown that the miR-29 family is involved in regulating type I collagen expression by interacting with the 3'UTR of its mRNA. Here, we investigated the roles of miR-29b in the activation of mouse primary-cultured hepatic stellate cells (HSCs), a principal collagen-producing cell in the liver. Expression of miR-29b was found to be down-regulated during HSC activation in primary culture. Transfection of a miR-29b precursor markedly attenuated the expression of Col1a1 and Col1a2 mRNAs and additionally blunted the increased expression of alpha-SMA, DDR2, FN1, ITGB1, and FDGFR-beta, which are key genes involved in the activation of HSCs. Further, overexpression of miR-29b led HSCs to remain in a quiescent state, as evidenced by their quiescent star-like cell morphology. Although phosphorylation of FAK, ERK, and Akt, and the mRNA expression of c-jun was unaffected, miR-29b overexpression suppressed the expression of c-fos mRNA. These results suggested that miR-29b is involved in the activation of HSCs and could be a candidate molecule for suppressing their activation and consequent liver fibrosis. (C) 2011 Elsevier Inc. All rights reserved.
  • Usefulness of transient elastography for assessment of liver fibrosis in chronic hepatitis B: Regression of liver stiffness during entecavir therapy, Masaru Enomoto, Mami Mori, Tomohiro Ogawa, Hideki Fujii, Sawako Kobayashi, Shuji Iwai, Hiroyasu Morikawa, Akihiro Tamori, Hiroki Sakaguchi, Ayumi Sawada, Setsuko Takeda, Daiki Habu, Susumu Shiomi, Norifumi Kawada, HEPATOLOGY RESEARCH, HEPATOLOGY RESEARCH, 40(9), 853 - 861, Sep. 2010
    Summary:Aim: The usefulness of transient elastography remains to be validated in chronic hepatitis B, particularly as a tool for monitoring the degree of liver fibrosis during treatment. Methods: The subjects were 50 patients with chronic hepatitis B virus infection. Liver biopsy was performed in 38 patients, and in 12 patients with platelet counts of 50 x 109/L or less, cirrhosis was clinically diagnosed on the basis of specific signs of portal hypertension. Liver stiffness was measured by transient elastography at baseline and after 12 months of treatment in 20 nucleos(t)ide-naive patients who started entecavir within 3 months after study entry. Results: Twenty (40%) patients were classified as F1, 10 (20%) as F2, 5 (10%) as F3, and 15 (30%) as F4 (cirrhosis). Median liver stiffness (interquartile range) was 7.0 kPa (5.6-9.4), 9.8 kPa (5.6-14.7), 9.8 kPa (7.6-12.9), and 17.3 kPa (8.2-27.6) in fibrosis stages F1 to F4, respectively. Liver stiffness significantly correlated with fibrosis stage (r = 0.46; P = 0.0014). Of the patients who started entecavir, median liver stiffness significantly decreased from 11.2 kPa (7.0-15.2) to 7.8 kPa (5.1-11.9; P = 0.0090) during 12 months of treatment. Median levels of amino-terminal peptide of type III procollagen and type IV collagen 7S domain in serum significantly decreased from 0.9 (0.6-1.3) to 0.6 (0.5-0.7) U/mL (P = 0.0010) and from 5.0 (4.4-6.7) to 3.9 (3.2-4.4) ng/mL (P = 0.015), respectively. Conclusion: Liver stiffness measurement can be useful for monitoring regression of liver fibrosis during entecavir treatment in patients with chronic hepatitis B virus infection.
  • A Human-Type Nonalcoholic Steatohepatitis Model with Advanced Fibrosis in Rabbits, Tomohiro Ogawa, Hideki Fujii, Katsutoshi Yoshizato, Norifumi Kawada, AMERICAN JOURNAL OF PATHOLOGY, AMERICAN JOURNAL OF PATHOLOGY, 177(1), 153 - 165, Jul. 2010
    Summary:Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis, which can lead to life-threatening liver failure and the development of hepatocellular carcinoma. The aim of the present study was to create a rabbit model of NASH with advanced fibrosis (almost cirrhosis) by feeding the animals a diet supplemented with 0.75% cholesterol and 12% corn oil. After 9 months of feeding with this diet, the rabbits showed high total cholesterol levels in serum and liver tissues in the absence of insulin resistance. The livers became whitish and nodular. In addition, the number of rabbit macrophage antigen-positive cells and the expression of mRNAs for inflammatory cytokines showed a significant increase. Moreover, fibrotic septa composed of collagens and a-smooth muscle actin-positive cells were found between the central and portal veins, indicating alteration of the parenchymal architecture. There was also a marked increase of mRNAs for transforming growth factor-beta 1 and collagen 1A1. Comprehensive analysis of protein and gene expression revealed an imbalance of the antioxidant system and methionine metabolism. We also found that ezetimibe attenuated steatohepatitis in this model. In conclusion, the present rabbit model of NASH features advanced fibrosis that is dose to cirrhosis and may be useful for analyzing the molecular mechanisms of human NASH. Ezetimibe blunted the development of NASH in this model, suggesting its potential clinical usefulness for human steatohepatitis. (Am J Pathol 2010, 177:153-165; DOI: 10.2353/ajpath.2010.090895)
  • Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine-choline-deficient diet, Yong-ping Mu, Tomohiro Ogawa, Norifumi Kawada, LABORATORY INVESTIGATION, LABORATORY INVESTIGATION, 90(2), 245 - 256, Feb. 2010
    Summary:Fatty liver disease has become a health problem related to metabolic syndrome worldwide, although its molecular pathogenesis requires further study. It is also unclear whether advanced fibrosis of steatohepatitis will regress when diet is controlled. The aim of this study was to investigate whether the resolution of fibrosis occurs in steatohepatitis induced by a methionine-choline-deficient diet (MCDD). Manifestation of endoplasmic reticulum (ER) stress in this model was also studied. Nonalcoholic steatohepatitis with advanced fibrosis was induced in rats by feeding them an MCDD for 10 weeks. Instead of MCDD, a methionine-choline control diet (CD) was given for the last 2 weeks to the experimental group. Fibrosis and inflammation were determined by tissue staining. Protein and gene expressions were determined by immunoblotting and quantitative reverse transcription-PCR (RT-PCR), respectively. Expressions of caspase-7, caspase-12, glucose-regulated protein 78 (GRP78), and protein disulfide isomerase were evaluated to clarify the presence of ER stress. Changing the diet from MCDD to CD triggered the reduction of fat in hepatocytes, a decrease in inflammatory gene expression and oxidative stress, and regression of fibrosis accompanied by the disappearance of activated stellate cells and macrophages. Immunohistochemistry, immunoblotting, and RT-PCR analysis all indicated the occurrence of ER stress in steatohepatitis, while it recovered immediately after changing the diet from MCCD to CD. The ratio of hepatocyte proliferation/apoptotis increased significantly during the recovery stage. This simple experiment clearly shows that changing the diet from MCDD to a normal diet (CD) triggers the resolution of hepatic inflammatory and fibrotic reactions and hepatocyte apoptosis, suggesting that MCDD-induced steatohepatitis is also reversible. ER stress appears and disappears in association with the generation and regression of steatohepatitis, respectively, with fibrosis. Laboratory Investigation (2010) 90, 245-256; doi:10.1038/labinvest.2009.123; published online 30 November 2009
  • Suppression of type I collagen production by microRNA-29b in cultured human stellate cells, Tomohiro Ogawa, Masashi Iizuka, Yumiko Sekiya, Katsutoshi Yoshizato, Kazuo Ikeda, Norifumi Kawada, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 391(1), 316 - 321, Jan. 2010
    Summary:MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression through imperfect base pairing with the 3' untranslated region (3'UTR) of target mRNA. We Studied the regulation of alpha 1 (1) collagen (Col1A1) expression by miRNAs in human stellate cells. which are involved in liver fibrogenesis. Among miR-29b, -143, and -218, whose expressions were altered in response to transforming growth factor-beta 1 or interferon-alpha stimulation, miR-29b was the most effective Suppressor of type I collagen at the mRNA and protein level via its direct binding to Col1A1 3'UTR miR-29b also had an effect on SP1 expression These results suggested that miR-29b is involved in the regulation of type I collagen expression by interferon-alpha in hepatic stellate cells. It is anticipated that miR-29b will be used for the regulation of stellate cell activation and lead to antifibrotic therapy (C) 2009 Elsevier Inc All rights reserved.
  • alpha-Tocopheryl succinate induces rapid and reversible phosphatidylserine externalization in histiocytic lymphoma through the caspase-independent pathway, Hirofumi Fujita, Daisuke Shiva, Toshihiko Utsumi, Tetsuya Ogino, Tomohiro Ogawa, Koichi Abe, Tatsuji Yasuda, Kozo Utsumi, Junzo Sasaki, MOLECULAR AND CELLULAR BIOCHEMISTRY, MOLECULAR AND CELLULAR BIOCHEMISTRY, 333(1-2), 137 - 149, Jan. 2010
    Summary:Phosphatidylserine (PS) externalization is a key feature of apoptotic cell death and plays an important role in clearance of apoptotic cells by phagocytes. PS externalization during apoptosis is generally an irreversible event mediated by caspase activation and is accompanied by other apoptotic events. We report here that an apoptosis inducer alpha-tocopheryl succinate (TOS) can induce PS externalization that is independent of apoptosis and reversible in the absence of fetal bovine serum (FBS) in histiocytic lymphoma U937 cells. In the presence of FBS, TOS induced PS externalization via a caspase-dependent mechanism accompanied by mitochondrial depolarization, cell shrinkage, increase of caspase-3 activity, and chromatin condensation. In contrast, in the absence of FBS, TOS induced the rapid PS externalization which was not accompanied by other apoptotic events. The PS externalization was reversible by removing TOS and was not involved in Ca(2+)-dependent scramblase activation and thiol oxidation of aminophospholipid translocase. A similar PS externalization was also induced by cholesteryl hemisuccinate (CS), the other succinate ester. These results suggested that the mechanism of TOS- and CS-induced PS externalization in the absence of FBS was different from it occurring during typical apoptosis.
  • Effect of natural interferon alpha on proliferation and apoptosis of hepatic stellate cells, Tomohiro Ogawa, Norifumi Kawada, Kazuo Ikeda, HEPATOLOGY INTERNATIONAL, HEPATOLOGY INTERNATIONAL, 3(3), 497 - 503, Sep. 2009
    Summary:Inhibition of the proliferation of hepatic stellate cells (HSC) is clinically important for the control of liver fibrosis and cirrhosis. Interferons are now frequently used for chronic viral hepatitis because of their anti-viral activity. However, patients treated with interferons exhibit a regression of liver fibrosis even if viral eradication is not achieved, indicating that interferon itself has anti-fibrotic activity. Herein, we show the anti-proliferation and pro-apoptotic activity of natural interferon alpha against HSC. We found that interferon alpha inhibited serum-stimulated [(3)H]thymidine incorporation of HSC in a dose-dependent manner, with a significant reduction at more than 100 U/ml. Interferon alpha also attenuated PDGF-BB-stimulated DNA synthesis of HSC. Although the molecular mechanism behind these phenomena has not been defined, we found that interferon alpha triggers the apoptosis of HSC treated with low-dose tumor necrosis factor alpha, as determined by the Alamar blue assay, morphology, and DNA ladder formation. Furthermore, interferon alpha decreased inhibitor of caspase-activated DNase (ICAD) levels, which may augment tumor necrosis factor alpha-induced cell death signals. Thus, interferon alpha regulates the number of myofibroblastic hepatic stellate cells and may clinically contribute to the regression of human liver fibrosis.
  • Induction of tropomyosin during hepatic stellate cell activation and the progression of liver fibrosis, Kohji Otogawa, Tomohiro Ogawa, Ryoko Shiga, Kazuo Ikeda, Norifumi Kawada, HEPATOLOGY INTERNATIONAL, HEPATOLOGY INTERNATIONAL, 3(2), 378 - 383, Jun. 2009
    Summary:The activation of hepatic stellate cells (HSCs) is a cue to initiate liver fibrosis. Activated stellate cells acquire contractile activity similar to pericytes and myofibroblasts in other organs by inducing the contractile machinery of cytoskeletons such as smooth muscle alpha-actin (alpha-SMA), a well-known marker of activated stellate cells, and actin-binding proteins. We further show herein the expression of tropomyosin in rat HSCs in the course of their activation during primary culture and liver tissue damaged by thioacetamide intoxication. In immunoblot analysis, tropomyosin became detectable in an early stage of the primary culture of rat stellate cells in a manner similar to the expression of alpha-SMA and platelet-derived growth factor receptor-beta. Tropomyosin was found to be colocalized with alpha-SMA on fluorescent immunocytochemistry. At the liver tissue level, an increased expression of tropomyosin was observed by immunoblot analysis and immunohistochemistry along the septum of fibrosis, where alpha-SMA was enriched. These results strongly suggest that tropomyosin is a new marker of activated stellate cells and may serve as a useful diagnostic marker of liver fibrosis.
  • Pleiotrophin inhibits transforming growth factor beta 1-induced apoptosis in hepatoma cell lines, Tae Jun Park, Bo Ra Jeong, Chise Tateno, Hong Seok Kim, Tomohiro Ogawa, In Kyoung Lim, Katsutoshi Yoshizato, MOLECULAR CARCINOGENESIS, MOLECULAR CARCINOGENESIS, 47(10), 784 - 796, Oct. 2008
    Summary:Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. in this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor beta 1 (TGF beta 1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGF beta 1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGF beta 1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGF beta 1-reluctant cells. The TGF beta 1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGF beta 1 activity during liver fibrosis. (C) 2008 Wiley-Liss, Inc.
  • Attenuation of acute and chronic liver injury in rats by iron-deficient diet, Kohji Otogawa, Tomohiro Ogawa, Ryoko Shiga, Kazuki Nakatani, Kazuo Ikeda, Yuji Nakajima, Norifumi Kawada, AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 294(2), R311 - R320, Feb. 2008
    Summary:Oxidative stress due to iron deposition in hepatocytes or Kupffer cells contributes to the initiation and perpetuation of liver injury. The aim of this study was to clarify the association between dietary iron and liver injuries in rats. Liver injury was initiated by the administration of thioacetamide or ligation of the common bile duct in rats fed a control diet (CD) or iron-deficient diet (ID). In the acute liver injury model induced by thioacetamide, serum levels of aspartate aminotransferase and alanine aminotransferase, as well as hepatic levels of lipid peroxide and 4-hydroxynonenal, were significantly decreased in the ID group. The expression of 8-hydroxydeoxyguanosine and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling positivity showed a similar tendency. The expression of interleukin-1 beta and monocyte chemotactic protein-1 mRNA was suppressed in the ID group. In liver fibrosis induced by an 8-wk thioacetamide administration, ID suppressed collagen deposition and smooth muscle beta-actin expression. The expressions of collagen 1A2, transforming growth factor beta, and platelet-derived growth factor receptor beta mRNA were all significantly decreased in the ID group. Liver fibrosis was additionally suppressed in the bile-duct ligation model by ID. In culture experiments, deferoxamine attenuated the activation process of rat hepatic stellate cells, a dominant producer of collagen in the liver. In conclusion, reduced dietary iron is considered to be beneficial in improving acute and chronic liver injuries by reducing oxidative stress. The results obtained in this study support the clinical usefulness of an iron-reduced diet for the improvement of liver disorders induced by chronic hepatitis C and alcoholic/nonalcoholic steatohepatitis.

Conference Activities & Talks

  • Identification of integrin alpha8 as a specific surface marker for liver mesenchymal cells that negatively regulate maturation of liver progenitor cells in development, 20th Annual Pathology Conference,   2017 03
  • Induction of MicroRNA-221/222 in the Progression of Liver Fibrosis Caused by Chronic Hepatitis C Virus Infection, 10th JSH Single Topic Conference, “Hepatitis C: Best Practice Based on Science”,   2012 11 , 10th JSH Single Topic Conference, “Hepatitis C: Best Practice Based on Science”
  • Micro RNA profiling in activated stellate cells, 2012 ISBRA World Congress,   2012 09 , 2012 ISBRA World Congress
  • Role of CYGB in human HCC and in animal model of carcinogenesis,   2012 06
  • Tumor formation and the role of Cygb in DEN-mediated carcinogenesis,   2011 12
  • Changes in sequences of core region, ISDR and IRRDR of the HCV genotype 1 during and after interferon alpha and ribavirin therapy, and efficacy of retreatment., 62nd AASLD,   2011 11 , 62nd AASLD
  • Indication of the Activation of Stellate Cells and the Progression of Liver Fibrosis by MicroRNA-222, 62nd AASLD,   2011 11 , 62nd AASLD

Research Grants & Projects

  • Basic Science Research Program, Study on liver fibrosis mechanism