研究者詳細 - 寺井　崇二

再生医療の最前線肝硬変症に対する骨髄由来細胞を用いた再生療法

寺井崇二, 高見太郎, 坂井田功

日本内分泌学会雑誌 89 ( 2 ) 723 - 723 2013年9月

NASH発症におけるhepatic crown-like structureの意義

伊藤美智子, 菅波孝祥, 小沼邦葉, 丸本芳雄, 寺井崇二, 佐久川廣, 坂井田功, 小川佳宏

肥満研究 19 ( Suppl. ) 156 - 156 2013年9月

当科における肝細胞癌に対するソラフェニブ(SF)治療の検証

花園忠相, 浦田洋平, 岩本拓也, 佐伯一成, 日高勲, 丸本芳雄, 石川剛, 高見太郎, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 62 ( 3 ) 175 - 175 2013年8月

The expanding role of fish models in understanding non-alcoholic fatty liver disease 査読

Yoichi Asaoka, Shuji Terai, Isao Sakaida, Hiroshi Nishina

DISEASE MODELS & MECHANISMS 6 ( 4 ) 905 - 914 2013年7月

記述言語：英語出版者・発行元：COMPANY OF BIOLOGISTS LTD

Non-alcoholic fatty liver disease (NAFLD) is a condition in which excessive fat accumulates in the liver of an individual who has not consumed excessive alcohol. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to hepatic cirrhosis and/or hepatocellular carcinoma (HCC). NAFLD is considered to be a hepatic manifestation of metabolic syndrome, and its incidence has risen worldwide in lockstep with the increased global prevalence of obesity: Over the last decade, rodent studies have yielded an impressive list of molecules associated with NAFLD and NASH pathogenesis. However, the identification Of currently unknown metabolic factor using Mammalian model Organisms is inefficient and expensive compared with studies using fish models such as zebrafish (Danio rerio) and medaka I (Oryzias latipes): Substantial advances in unraveling the molecular pathogenesis of NAFLD have recently been achieved through unbiased forward genetic screens using small fish models. Furthermore, these easily manipulated organisms have been used to great advantage to evaluate the therapeutic effectiveness of various chemical compounds for the treatment of NAFLD. In this Review, we summarize aspects of NAFLD (specifically focusing on NASH) pathogenesis that have been previously revealed by rodent models, and discuss how small fish are increasingly being used to uncover factors that contribute to normal hepatic lipid metabolism. We describe the various types of fish models in use for this purpose, including those generated by Mutation, transgenesis, or dietary or chemical treatment, and contrast them with rodent models. The use of small fish in identifying novel potential therapeutic agents for the treatment of NAFLD and NASH is also addressed.

DOI： 10.1242/dmm.011981

【細胞移植】肝硬変症に対する自己骨髄由来培養髄細胞を用いた再生細胞療法

寺井崇二, 高見太郎, 坂井田功

細胞 45 ( 7 ) 327 - 329 2013年7月

記述言語：日本語出版者・発行元：(株)ニュー・サイエンス社

平成25年4月26日、再生医療推進法が成立した。同法は生命倫理に配慮しつつ、安全な研究開発や普及に向けて総合的に取り組むことを基本理念に盛りこみ、再生医療の普及を促進する施策を策定・実施する責務が国にあると明記されている。我々は基礎研究を進め、2003年より肝硬変症に対する自己骨髄細胞投与療法の研究開発を世界に先駆け実施しその有効性を明らかにしてきた。さらに低侵襲の再生療法を開発するため、自己骨髄由来培養細胞を用いた再生医療開発を行っている。本特集では我々が実施してきた研究開発について概説する。(著者抄録)

Correlations between Obesity/Metabolic Syndrome-Related Factors and Risk of Developing Colorectal Tumors 査読

Satoko Harima, Shinichi Hashimoto, Hiroaki Shibata, Takaharu Matsunaga, Ryo Tanabe, Shuji Terai, Isao Sakaida

HEPATO-GASTROENTEROLOGY 60 ( 124 ) 733 - 737 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: Colorectal cancer/adenoma development may correlate with obesity/metabolic syndrome in the Japanese. We sought to clarify the relation between colorectal adenoma prevalence and various factors to develop a better colorectal tumor screening strategy Methodology: Of 2668 patients who underwent colonoscopy, medical records of 837 patients (467 men, 370 women; age, 40-80 years) with available data on measured values of body mass index, waist circumference, body fat percentage, and prior history of hypertension, diabetes and hyperlipidemia were reviewed and analyzed. Results: Of these patients, 460 (55.0%) had colorectal tumor or prior history thereof (lesions >= 1mm), Multivariate analysis revealed significant differences in gender, age and waist circumference between patients with/without colorectal adenoma, with men at significantly higher risk than women of developing colorectal tumor (OR=2.57, 95% CI: 1.84-4.65; p<0.001), In patients with/without colorectal tumor, age, waist circumference and body fat percentage were significantly different among men, but only age was significantly different among women. Conclusions: Present findings that waist circumference and body fat percentage correlated with prevalence of colorectal tumor among men may contribute to more accurate prediction of colorectal tumor risk and an efficient colorectal cancer screening system.

DOI： 10.5754/hge12895

Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis 査読

Issei Saeki, Shuji Terai, Koichi Fujisawa, Taro Takami, Naoki Yamamoto, Toshihiko Matsumoto, Yoshikazu Hirose, Yasuhiko Murata, Takahiro Yamasaki, Isao Sakaida

Journal of Gastroenterology 48 ( 6 ) 738 - 750 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Human hepatocellular carcinoma (HCC) is highly ubiquitinated. The ubiquitination is important to the generatation of HCC. The antitumor and antifibrosis effects of an ubiquitin-proteasome system inhibitor, bortezomib, on HCC with liver cirrhosis (LC) were analyzed in vitro and in vivo. Methods: The effect of bortezomib was analyzed in the rat hepatocarcinogenesis model using a DEN and CDAA diet (DEN/CDAA model), which shows severe LC and generation of HCC. The decrease of GST-P-positive foci and HCC were analyzed in vivo. Cell death was analyzed by cell death detection kit. Liver fibrosis was checked by sirius-red staining and α-smooth muscle actin staining. The in vitro study involved 3 HCC cell lines (HepG2, HuH7, and HLF) and primary rat and human hepatocytes. The proliferation rate of the HCC cell line was analyzed using the MTT assay and FACS analysis. The toxicity of bortezomib was checked using the LDH release assay for primary human and rat hepatocytes. Results: In the rat hepatocarcinogenesis model, bortezomib prevented the development of preneoplastic lesions during the early stages of hepatocarcinogenesis and specifically induced cell death in HCC. Furthermore, bortezomib inhibited cell proliferation and induced tumor-specific cell death in HCC cell lines with decrease of cyclin D1 and phospho-Rb expression. Further, bortezomib showed no hepatotoxicity of primary rat and human hepatocytes, suggesting that it might be an HCC-specific drug. Bortezomib also prevented the activation of hepatic stellate cells and inhibited the liver fibrosis of the DEN/CDAA model. Conclusions: Bortezomib appears to be an ideal target drug for HCC with LC. © 2012 Springer.

DOI： 10.1007/s00535-012-0675-z

Scopus

チロシンは、C型慢性肝障害におけるインスリン抵抗性の新たなバイオマーカーとなり得る

在津潤一, 山崎隆弘, 佐伯一成, 岩本拓也, 播磨夕美子, 丸本芳雄, 日高勲, 浦田洋平, 石川剛, 高見太郎, 瀬川誠, 内田耕一, 寺井崇二, 坂井田功

肝臓 54 ( Suppl.1 ) A238 - A238 2013年4月

短期間で興味深いエコー像変化を呈した肝細胞癌の一例

佐伯一成, 日高勲, 松永一仁, 高見太郎, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 40 ( Suppl. ) S534 - S534 2013年4月

当科における肝細胞癌に対するソラフェニブ治療の検証とくに肝予備能と病勢制御に着目して

浦田洋平, 山崎隆弘, 佐伯一成, 岩本拓也, 播磨夕美子, 日高勲, 石川剛, 高見太郎, 内田耕一, 寺井崇二, 坂井田功

肝臓 54 ( Suppl.1 ) A284 - A284 2013年4月

Bone-marrow-derived cells cultured in serum-free medium reduce liver fibrosis and improve liver function in carbon-tetrachloride-treated cirrhotic mice 査読

Takuya Iwamoto, Shuji Terai, Takuro Hisanaga, Taro Takami, Naoki Yamamoto, Shoko Watanabe, Isao Sakaida

CELL AND TISSUE RESEARCH 351 ( 3 ) 487 - 495 2013年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We have previously developed autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis patients. One problem associated with ABMi therapy is that general anesthesia is required to obtain 400 ml bone marrow fluid from liver cirrhosis patients. However, many patients with decompensated cirrhosis do not meet the criteria, because of decreased liver function or an increased bleeding tendency. To overcome these issues, our aim is to derive liver repair cells from small amounts of autologous bone marrow aspirates obtained under local anesthesia and to use these cells in liver cirrhosis patients. Here, we conducted, by using a mouse model, basic research aimed at achieving novel liver regeneration therapy. We cultured bone marrow cells aspirated from the femurs of C57 BL/6 Tg14 (act-EGFP) OsbY01 mice (green fluoresent protein [GFP]-transgenic mice). After 14 days of culture with serum-free medium (good manufacturing practice grade), the obtained spindle-shaped GFP-positive cells were injected (1x10(4) cells) via the caudal vein into mice with carbon tetrachloride (CCl4)-induced cirrhosis. Numerous cultured macrophages and some mesenchymal stem cells repopulated the cirrhotic liver. The results showed that serum albumin, liver fibrosis and liver function were significantly improved in the group treated with cultured bone marrow cells (P < 0.01). Moreover, matrix metalloproteinase-9 expression was increased in the liver (P < 0.01). Thus, infusion of bone-marrow-derived cultured cells improved liver function and liver fibrosis in mice with CCl4-induced cirrhosis.

DOI： 10.1007/s00441-012-1528-z

【肝疾患と幹細胞をめぐる進歩】骨髄細胞投与による肝硬変症に対する肝再生・発癌抑制療法

高見太郎, 前田雅喜, 寺井崇二, 坂井田功

消化器内科 56 ( 3 ) 324 - 330 2013年3月

Crohn 病の経過中に非アルコール性脂肪性肝炎(NASH)から非代償性肝硬変へと進展した一例

田邉規和, 播磨夕美子, 橋本真一, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 62 ( 1 ) 33 - 37 2013年2月

記述言語：日本語出版者・発行元：山口大学医学会

症例は31歳の女性.18歳時にCrohn病と診断され,当科での治療を開始された.経腸栄養療法や5-ASA製剤,ステロイドや抗TNFα抗体製剤等の内科的治療を行うも効果不十分であり,消化管合併症の悪化から24歳時に回腸部分切除術,26歳時に回盲部切除術,28歳時に回腸および上行結腸切除術を施行し,残存小腸は約280cmとなった.その後も症状は安定せず,成分栄養剤による経腸栄養療法を勧めるも患者の理解が得られず,長期の絶食および中心静脈栄養を施行していた.31歳時頃より,見当識障害および活動性低下が認められたため当科入院となった.腹部骨盤単純CT検査上,肝萎縮を伴う肝硬変の状態と考えられ,血液生化学検査にて著明な肝機能障害およびアンモニア値の上昇を認めたため,非代償性肝硬変症による肝性脳症と診断された.血液検査上HBVおよびHCV感染は否定され,飲酒歴もなく,以前より脂肪肝が認められ,肝胆道系酵素の上昇も認められていたことから,非アルコール性脂肪性肝炎(NASH)による非代償性肝硬変と診断した.年齢と肝機能から肝移植を考慮したが,適したドナーがいなかったことと,患者が肝移植を希望しなかったことから対症療法を継続した.その後もCrohn病や肝硬変の加療で入退院を繰り返し肝不全により死亡した.重症Crohn病の経過中に複数の要因からNASHを併発し非代償性肝硬変症へ進展した,極めてまれな症例を経験したため報告する.The patient was a 31-year-old woman who had been diagnosed with Crohn's disease at age 18 years. Enteral nutrition and medical treatment were given, but their effect was insufficient. Gastrointestinal complications worsened, and ileocecal resection was performed three times. The remaining small intestine was 280 cm. But, her symptoms were unstable. Thus long-term fasting and central venous nutrition were adopted. At 31 years old, she was hospitalized with cognitive dysfunction and decreased activity. CT scan showed liver cirrhosis(LC),and hepatic dysfunction and an elevated ammonia level were seen on blood tests. Therefore, she was diagnosed as hepatic encephalopathy from decompensated LC. Blood tests were negative for HBV and HCV infections, she had no history of drinking alcohol, fatty liver had been presented for some time, and elevated transaminase were seen. This led to a diagnosis of LC resulting from non-alcoholic steatohepatitis(NASH).Liver transplantation was considered, but there was no appropriate donor, and the patient did not desire. Therefore, symptomatic therapy was continued. She was repeatedly hospitalized and finally died from liver failure. We report that the rare case in which NASH occurred due to multiple factors during the course of severe Crohn's disease and progressed to decompensated LC.

DOI： 10.2342/ymj.62.33

CiNii Article

J-GLOBAL

Medaka fish, Oryzias latipes, as a model for human obesity-related glomerulopathy 査読

Koichiro Ichimura, Yusuke Kawashima, Tomomi Nakamura, Rebecca Powell, Yuya Hidoh, Shuji Terai, Isao Sakaida, Yoshio Kodera, Takashi Tsuji, Jian-Xing Ma, Tatsuo Sakai, Hiroyuki Matsumoto, Tomoko Obara

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 431 ( 4 ) 712 - 717 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Obesity, an ongoing significant public health problem, is a part of complex disease characterized as metabolic syndrome. Medaka and zebrafish are useful aquatic experimental animals widely used in the field of toxicology and environmental health sciences and as a human disease models. In medaka, simple feeding of a high fat diet (HFD) can induce body weight gain, excessive accumulation of visceral adipose tissue, hyperglycemia, hyperlipidemia, and steatohepatitis, which mimics human metabolic syndrome. In the present study, to explore the possibility that the adult medaka fed with HFD (HFD-medaka) can be used as an animal model for human metabolic syndrome-associated glomerular disease, including obesity-related glomerulopathy (ORG), we analyzed structural alterations and protein expression in the mesonephric kidney of HFD-medaka. We found that the histopathology was consistent with glomerulomegaly accompanied by the dilation of glomerular capillaries and proliferative expansion of the mesangium, a condition partially comparable to human ORG. Moreover, expressions of several kinds of kidney disease-related proteins (such as MYH9, SM22 alpha) were significantly elevated. Thus, the HFD-medaka has a high potential as an animal model useful for exploring the mechanism underling human ORG. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.01.053

【再生医療の実現化に向けて】肝硬変症に対する自己骨髄細胞投与療法

消化器領域における幹細胞研究の進歩培養骨髄由来細胞を用いた肝硬変症に対する修復療法の開発へのProof of Concept

寺井崇二, 高見太郎, 坂井田功

日本消化器病学会雑誌 110 ( 臨増総会 ) A83 - A83 2013年2月

丸本美穂, 寺井崇二, 丸本芳雄, 高見太郎, 坂井田功

炎症と免疫 21 ( 2 ) 142 - 147 2013年2月

記述言語：日本語出版者・発行元：(株)先端医学社

難治性肝疾患に対する新たな治療法の開発をめざして、われわれは骨髄幹細胞の可塑性に着目し基礎研究を進めてきた。慢性炎症という環境下において骨髄細胞が肝細胞へと分化し、さらにその過程で肝合成能・肝線維化・生命予後が有意に改善するという動物実験の結果を基盤として、2003年11月より肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)の臨床研究を開始するに至った。その結果、肝機能改善・修復効果を確認し、さらに国内外からABMi療法の安全性および有効性が追加報告されるなど、自己骨髄細胞を用いた肝硬変に対する再生治療の有効性が明らかになった。今後はより低侵襲な骨髄由来培養細胞を用いた新たな治療法の開発もおこなっていく。(著者抄録)

An improvement of liver cirrhosis classification using ultrasonic images

肝線維化の診断と臨床自己骨髄細胞による肝硬変に対する再生修復療法の現状と展望

高見太郎, 寺井崇二, 坂井田功

Japanese Journal of Diagnostic Imaging 31 ( 1 ) 30 - 30 2013年2月

Hayashi, T., Fujita, Y., Mitani, Y., Hamamoto, Y., Segawa, M., Terai, S., Sakaida, I.

IEEJ Transactions on Electronics, Information and Systems 133 ( 2 ) 289 - 296 2013年1月

掲載種別：研究論文（学術雑誌）

Ultrasonic images have been widely used for diagnosis of liver cirrhosis. In practice, there are significant differences in the result of a diagnosis among individuals for physician's experiences. Therefore, the objective and quantitative method for diagnosis is needed. The quality of M-mode image is in general low. Thus, it is very difficult to diagnose liver cirrhosis with M-mode images. In cirrhosis classification using the ultrasonic M-mode image, Zhou's method was proposed. In this paper, compared with the Zhou's method, we propose a method using weighted autocorrelation coefficient to extract an abdominal aorta wall. Furthermore, we propose the use of a bilateral filter to improve the quality of the M-mode images. The bilateral filter is expected to be effective one of smoothing filters preserving an edge to improve image quality in an ultrasonic image. The experimental results show that the weighted autocorrelation coefficient approach leads to improvement in the performance of the abdominal aorta wall extraction and moreover the bilateral filter is effective in both the abdominal aorta wall extraction and cirrhosis classification. © 2013 The Institute of Electrical Engineers of Japan.

DOI： 10.1541/ieejeiss.133.289

Scopus

肝臓肝臓の再生療法

高見太郎, 寺井崇二, 坂井田功

Annual Review消化器 2013 196 - 202 2013年1月

記述言語：日本語出版者・発行元：(株)中外医学社

これまで肝硬変症を対象とした肝臓再生療法として,自己骨髄単核球細胞,G-CSF誘導末梢血CD34陽性細胞や骨髄間葉系幹細胞投与が実施され,一部の症例で改善したとの報告がある.われわれも,マウス基礎研究により自己骨髄細胞投与が肝線維化および肝機能を改善させることを報告し,その成果を基盤にした臨床研究「肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)」でも肝機能改善・修復効果を確認した.さらに国内外からABMi療法の安全性・有効性が追試報告されるなど,自己骨髄由来細胞を用いた肝硬変症に対する再生療法の有効性が強く示唆された.今後は,エビデンスレベルの高い有効性を示すためのランダマイズドコントロールスタディの実施や,低侵襲な骨髄由来培養細胞を用いた治療法の開発も必要となると思われる.(著者抄録)