The study of hepatocyte heterogeneity in chronic liver disease progression and oncogenesis

• Project/Area Number: 20K17038
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Yamazoe Taiji 国立研究開発法人国立国際医療研究センター, 肝炎・免疫研究センター, 肝疾患研究部 上級研究員 (20736219)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 細胞核画像解析 / 慢性肝疾患 / 空間的遺伝子解析 / シングルセル 調製法 / ヘテロ不均一 / 発がん

Outline of Research at the Start

マウスなどの実験動物に対する肝細胞のploidyに関する研究は散見されるものの、ヒトの生理学的な染色体量のheterogeneityや慢性肝障害時におけるploidyの変化や、その病態特異性・依存性は未だ明らかになっていない。本研究では、これまで検討されてなかったzonationおよび肝細胞倍数性の両面から、肝細胞群のheterogeneityに関して検討を加えるとともに、B型・C型肝炎ウイルス、アルコール性、非アルコール性脂肪性肝疾患など癌病変の素地となる慢性肝疾患横断的な検討を行うことで新たな知見を得ようとするものである。

Outline of Final Research Achievements

The aim of study is to reveal the relationship between the change of hepatocyte heterogeneity through liver disease progression and liver carcinogenesis. The hepatocytes shows the heterogeneity in terms of liver function and its morphology. In this study, we focused the ploidy as the DNA amount and gene expression in single cell levels. Utilized the liver resection samples, the size of nucleus in hepatocyte are measured by using the liver section with DAPI stain, and the gene expressions are measured by RNAseq. We used the VISIUM for spatial genomics and found the considerable variation in RNA quality, which makes difficult to obtain the differentially expressed genes (DEGs). This indicates the spatial genomics needs the good amount of sample size and the improvement of platform.

Academic Significance and Societal Importance of the Research Achievements

近年急速に発達しているシークエンス技術を応用したシングルセルRNAseq解析や空間的トランスクリプトーム解析により、以前は解析できなかった生理下あるいは病態下における１細胞の挙動を解析することが可能となり、次々と新しい知見が得られている。その一方で、これらの新しい技術の遂行には一定の経験が必要である。今回、遺伝子発現量解析をヒト由来試料で行うための改善点と注意点が明らかとなった。今後、解析プラットフォームも改善されており、ますます重要な解析方法となるため、解析経験と結果の共有が重要と考えられる。

Research Products

• [Journal Article] Differences in branched-chain amino acid to tyrosine ratio (BTR) among etiologies of chronic liver disease progression compared to healthy adults. (2024)
  • Author(s): Mino Masaaki、Sano Akitoshi、Kakazu Eiji、Matsubara Hiroko、Kakisaka Keisuke、Kogure Takayuki、Sekine Katsunori、Aoki Yoshihiko、Imamura Masatoshi、Matsuda Michitaka、Yamazoe Taiji、Mori Taizo、Yoshio Sachiyo、Inoue Jun、Masamune Atsushi、Kanto Tatsuya
  • Journal Title: Journal of Gastroenterology Volume: - Issue: 6 Pages: 483-493
  • DOI: 10.1007/s00535-024-02092-0
  • Peer Reviewed
• [Journal Article] Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model (2023)
  • Author(s): Tsutsui Yuriko、Mori Taizo、Yoshio Sachiyo、Sato Miku、Sakata Toshihiro、Yoshida Yuichi、Kawai Hironari、Yoshikawa Shiori、Yamazoe Taiji、Matsuda Michitaka、Kakazu Eiji、Osawa Yosuke、Oyama Chinatsu、Tamura-Nakano Miwa、Kawaguchi Takumi、Yoshizumi Tomoharu、Kanto Tatsuya
  • Journal Title: Hepatology Communications Volume: 7 Issue: 10
  • DOI: 10.1097/hc9.0000000000000236
  • Peer Reviewed / Open Access
• [Journal Article] Dried blood spot-based host genome analysis technique targeting pathological associations with hepatitis B: Development and clinical application in the Cambodian population. (2023)
  • Author(s): Setoyama H, Yamazoe T, Kanto T et al.
  • Journal Title: Hepatol Res Volume: 12 Issue: 12 Pages: 1147-1155
  • DOI: 10.1111/hepr.13949
  • Peer Reviewed / Open Access
• [Journal Article] Toll‐like receptor 7 agonist, GS‐986, is an immune‐stimulant inducing follicular helper T cells and expanding HBs antigen‐specific B cells <i>in vitro</i> (2023)
  • Author(s): Mori Taizo、Yoshio Sachiyo、Yoshikawa Shiori、Tsustui Yuriko、Sakata Toshihiro、Yoshida Yuichi、Sakamoto Yuzuru、Kawai Hironari、Osawa Yosuke、Yamazoe Taiji、Aoki Yoshihiko、Fletcher Simon P.、Kanto Tatsuya
  • Journal Title: Liver International Volume: 43 Issue: 6 Pages: 1213-1224
  • DOI: 10.1111/liv.15568
  • Peer Reviewed
• [Journal Article] Effects of sodium glucose cotransporter 2 inhibitors and pioglitazone on FIB‐4 index in metabolic‐associated fatty liver disease (2023)
  • Author(s): Mino Masaaki、Kakazu Eiji、Sano Akitoshi、Katsuyama Hisayuki、Hakoshima Mariko、Yanai Hidekatsu、Aoki Yoshihiko、Imamura Masatoshi、Yamazoe Taiji、Mori Taizo、Yoshio Sachiyo、Inoue Jun、Masamune Atsushi、Kanto Tatsuya
  • Journal Title: Hepatology Research Volume: - Issue: 7 Pages: 618-628
  • DOI: 10.1111/hepr.13898
  • Peer Reviewed
• [Journal Article] Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma (2023)
  • Author(s): Yamauchi Reika、Ito Takanori、Yoshio Sachiyo、Yamamoto Takafumi、Mizuno Kazuyuki、Ishigami Masatoshi、Kawashima Hiroki、Yasuda Satoshi、Shimose Shigeo、Iwamoto Hideki、Yamazoe Taiji、Mori Taizo、Kakazu Eiji、Kawaguchi Takumi、Toyoda Hidenori、Kanto Tatsuya
  • Journal Title: Journal of Gastroenterology Volume: - Issue: 6 Pages: 565-574
  • DOI: 10.1007/s00535-023-01985-w
  • Peer Reviewed
• [Journal Article] Peripheral‐dominant liver fibrosis and tumor distribution in a mouse model of congestive hepatopathy (2022)
  • Author(s): Kawai Hironari、Osawa Yosuke、et al.
  • Journal Title: Hepatology Research Volume: 53 Issue: 4 Pages: 370-376
  • DOI: 10.1111/hepr.13866
  • Peer Reviewed
• [Journal Article] Sphingosine‐1‐phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy (2021)
  • Author(s): Kawai H, Osawa Y, Matsuda M, Tsunoda T, Yanagida K, Hishikawa D, Okawara M, Sakamoto Y, Shimagaki T, Tsutsui Y, Yoshida Y, Yoshikawa S, Hashi K, Doi H, Mori T, Yamazoe T, Yoshio S, Sugiyama M, Okuzaki D, Komatsu H, Inui A, Tamura-Nakano M, Oyama C, Shindou H, Kusano H, Kage M, Ikegami T, Yanaga K, Kanto T
  • Journal Title: Hepatology Volume: - Issue: 1 Pages: 112-125
  • DOI: 10.1002/hep.32256
  • Peer Reviewed / Open Access
• [Journal Article] <i>MYC</i> Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma (2021)
  • Author(s): Maddipati R, et. al
  • Journal Title: Cancer Discovery Volume: 12 Issue: 2 Pages: 542-561
  • DOI: 10.1158/2159-8290.cd-20-1826
  • Peer Reviewed
• [Journal Article] Cluster of Differentiation 44 Promotes Liver Fibrosis and Serves as a Biomarker in Congestive Hepatopathy (2021)
  • Author(s): Osawa Y, Kawai H, Yamazoe T, Kanto T, et al.
  • Journal Title: Hepatology Communications Volume: 5 Issue: 8 Pages: 1437-1447
  • DOI: 10.1002/hep4.1721
  • Peer Reviewed / Open Access
• [Journal Article] Calcium signaling induces a partial EMT (2021)
  • Author(s): NorgardJason RJ, Yamazoe T, Stranger BZ, et al.
  • Journal Title: EMBO Reports Volume: - Issue: 9
  • DOI: 10.15252/embr.202051872
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phenotypic Characterization by Single-Cell Mass Cytometry of Human Intrahepatic and Peripheral NK Cells in Patients with Hepatocellular Carcinoma (2021)
  • Author(s): Yoshida Yuichi、Yoshio Sachiyo、Yamazoe Taiji、Mori Taizo、Tsustui Yuriko、Kawai Hironari、Yoshikawa Shiori、Fukuhara Takasuke、Okamoto Toru、Ono Yoshihiro、Takahashi Yu、Hashida Ryuki、Kawaguchi Takumi、Taketomi Akinobu、Kanto Tatsuya
  • Journal Title: Cells Volume: 10 Issue: 6 Pages: 1495-1495
  • DOI: 10.3390/cells10061495
  • Peer Reviewed / Open Access
• [Journal Article] Myostatin as a fibroblast‐activating factor impacts on postoperative outcome in patients with hepatocellular carcinoma (2021)
  • Author(s): Yoshio Sachiyo、Shimagaki Tomonari、Hashida Ryuki、Kawaguchi Takumi、Tsutsui Yuriko、Sakamoto Yuzuru、Yoshida Yuichi、Kawai Hironari、Yoshikawa Shiori、Yamazoe Taiji、Mori Taizo、Osawa Yosuke、Itoh Shinji、Fukai Moto、Yoshizumi Tomoharu、Taketomi Akinobu、Mori Masaki、Kanto Tatsuya
  • Journal Title: Hepatology Research Volume: 51 Issue: 7 Pages: 803-812
  • DOI: 10.1111/hepr.13667
  • Peer Reviewed / Open Access
• [Journal Article] Mutant p53 regulates Survivin to foster lung metastasis (2021)
  • Author(s): Tang Q.、Efe G.、Chiarella A.、Leung J.、Chen M.、Yamazoe T.、Su Z.、Pitarresi J.、Li J.、Islam M.、Karakasheva T.、Klein-Szanto A.、Pan S.、Hu J.、Natsugoe S.、Gu W.、Stanger B.、Wong K.、Diehl A.、Bass A.、Nakagawa H.、Murphy M.、Rustgi A.
  • Journal Title: Genes & Development Volume: 35 Issue: 7-8 Pages: 528-541
  • DOI: 10.1101/gad.340505.120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blood angiopoietin-2 predicts liver angiogenesis and fibrosis in hepatitis C patients (2021)
  • Author(s): Osawa Yosuke、Yoshio Sachiyo、Aoki Yoshihiko、Korenaga Masaaki、Imamura Masatoshi、Oide Takashi、Okawara Miku、Kawai Hironari、Tsutsui Yuriko、Yoshida Yuichi、Yoshikawa Shiori、Mori Taizo、Yamazoe Taiji、Kanto Tatsuya
  • Journal Title: BMC Gastroenterology Volume: 21 Issue: 1 Pages: 000-000
  • DOI: 10.1186/s12876-021-01633-8
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics (2020)
  • Author(s): Yamazoe Taiji、Mori Taizo、Yoshio Sachiyo、Kanto Tatsuya
  • Journal Title: Global Health & Medicine Volume: 2 Issue: 5 Pages: 273-281
  • DOI: 10.35772/ghm.2020.01089
  • NAID: 130007936750
  • ISSN: 2434-9186, 2434-9194
  • Year and Date: 2020-10-31
  • Open Access
• [Journal Article] Impact of Immune Reconstitution-Induced Hepatic Flare on Hepatitis B Surface Antigen Loss in Hepatitis B Virus/Human Immunodeficiency Virus-1 Coinfected Patients (2020)
  • Author(s): Yoshikawa Shiori、Yoshio Sachiyo、Yoshida Yuichi、Tsutsui Yuriko、Kawai Hironari、Yamazoe Taiji、Mori Taizo、Osawa Yosuke、Sugiyama Masaya、Iwamoto Masashi、Watashi Koichi、Kawaguchi Takumi、Akita Tomoyuki、Tanaka Junko、Kikuchi Yoshimi、Mizokami Masashi、Oka Shinichi、Kanto Tatsuya、Gatanaga Hiroyuki
  • Journal Title: The Journal of Infectious Diseases Volume: - Issue: 12 Pages: 2080-2089
  • DOI: 10.1093/infdis/jiaa662
  • Peer Reviewed
• [Journal Article] Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression (2020)
  • Author(s): Yuan Salina、Natesan Ramakrishnan、Sanchez-Rivera Francisco J.、Li Jinyang、Bhanu Natarajan V.、Yamazoe Taiji、Lin Jeffrey H.、Merrell Allyson J.、Sela Yogev、Thomas Stacy K.、Jiang Yanqing、Plesset Jacqueline B.、Miller Emma M.、Shi Junwei、Garcia Benjamin A.、Lowe Scott W.、Asangani Irfan A.、Stanger Ben Z.
  • Journal Title: Cancer Discovery Volume: 10 Issue: 6 Pages: 854-871
  • DOI: 10.1158/2159-8290.cd-19-1299
  • Peer Reviewed / Open Access
• [Presentation] HBV持続感染者の肝炎増悪期の末梢血単核細胞を用いたシングルセル解析 (2022)
  • Author(s): 山添太士、由雄祥代、考藤達哉
  • Organizer: 第58回日本肝臓学会総会
• [Presentation] 肝がん合併非アルコール性脂肪肝炎(NASH)における肝細胞倍体性変化の検討 (2020)
  • Author(s): 山添太士、吉田祐一、筒井由梨子、河合裕成、吉川詩織、森泰三、由雄祥代、大澤陽介、考藤達哉
  • Organizer: 第24回日本肝臓学会大会
• [Book] 肝臓クリニカルアップデート (2022)
  • Author(s): 山添太士、考藤達哉
  • Total Pages: 90
  • Publisher: 医学図書出版
• [Remarks] 肝炎・免疫研究センター 肝疾患研究部
  • URL: https://www.ncgmkohnodai.go.jp/kanen_meneki/index.html