Sato, Toshiro

写真a

Affiliation

School of Medicine, Department of Biochemistry （Shinanomachi）

Position

Professor

External Links
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Career 【 Display / hide 】

  • 1997.04
    -
    2003.03

    慶應義塾大学病院, 内科研修医

  • 2003.04
    -
    Present

    慶應義塾大学病院, 内科専修医

  • 2004.09
    -
    Present

    慶應義塾大学病院, COE特別研究員

  • 2005.09
    -
    Present

    東京電力病院, 消化器内科, 医員

  • 2006.04
    -
    Present

    Stowers研究所（米国）, 博士研究員

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Academic Background 【 Display / hide 】

  • 1997.03

    Keio University, 医学部

    University

  • 2003.03

    Keio University, 大学院医学研究科

    Graduate School, Withdrawal after completion of doctoral course requirements

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Academic Degrees 【 Display / hide 】

  • 博士（医学）慶應義塾大学大学院医学研究科, Keio University, 2004

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Licenses and Qualifications 【 Display / hide 】

  • 医師免許証, 1997.05

  • 日本内科学会　内科認定医, 1999.09

  • 日本消化器病学会　専門医, 2014.01

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Papers 【 Display / hide 】

  • Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

    Nakamoto N., Sasaki N., Aoki R., Miyamoto K., Suda W., Teratani T., Suzuki T., Koda Y., Chu P., Taniki N., Yamaguchi A., Kanamori M., Kamada N., Hattori M., Ashida H., Sakamoto M., Atarashi K., Narushima S., Yoshimura A., Honda K., Sato T., Kanai T.

    Nature Microbiology （Nature Microbiology)  4 （ 3 ） 492 - 503 2019.03

    　View Summary

    © 2019, The Author(s), under exclusive licence to Springer Nature Limited. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (T H 17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis and Enterococcus gallinarum, which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K. pneumoniae that was associated with bacterial translocation and susceptibility to T H 17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T H 17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.

  • Modeling Human Digestive Diseases With CRISPR-Cas9–Modified Organoids

    Fujii M., Clevers H., Sato T.

    Gastroenterology （Gastroenterology)  156 （ 3 ） 562 - 576 2019.02

    ISSN  00165085

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    © 2019 AGA Institute Insights into the stem cell niche have allowed researchers to cultivate adult tissue stem cells as organoids that display structural and phenotypic features of healthy and diseased epithelial tissues. Organoids derived from patients’ tissues are used as models of disease and to test drugs. CRISPR-Cas9 technology can be used to genetically engineer organoids for studies of monogenic diseases and cancer. We review the derivation of organoids from human gastrointestinal tissues and how CRISPR-Cas9 technology can be used to study these organoids. We discuss burgeoning technologies that are broadening our understanding of diseases of the digestive system.

  • Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition

    Fujii M., Matano M., Toshimitsu K., Takano A., Mikami Y., Nishikori S., Sugimoto S., Sato T.

    Cell Stem Cell （Cell Stem Cell)  23 （ 6 ） 787 - 793.e6 2018.12

    ISSN  19345909

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    © 2018 Elsevier Inc. Cellular diversity that shapes tissue architecture and function is governed by multiple niche signals. Nonetheless, maintaining cellular diversity in human intestinal organoids has been challenging. Based on niche ligands present in the natural stem cell milieu, we establish a refined organoid culture condition for intestinal epithelia that allows human intestinal organoids to concurrently undergo multi-differentiation and self-renewal. High-throughput screening reveals that the combination of insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2) enhances the clonogenic capacity and CRISPR-genome engineering efficiency of human intestinal stem cells. The combination equally enables long-term culture of a range of intestinal organoids, including rat small intestinal organoids. Droplet-based single-cell RNA sequencing further illustrates the conservation of the native cellular diversity in human small intestinal organoids cultured with the refined condition. The modified culture protocol outperforms the conventional method and offers a viable strategy for modeling human intestinal tissues and diseases in an in vivo relevant context. Sato and colleagues develop a modified culture condition for human intestinal organoids that improves the culture efficiency and maintains their long-term multi-differentiation capacity. scRNA-seq of human small intestinal crypts and organoids demonstrates that in vivo cellular diversity can be preserved in organoids cultured with the refined condition.

  • Induction of differentiation of intrahepatic cholangiocarcinoma cells to functional hepatocytes using an organoid culture system

    Saito Yoshimasa, Nakaoka Toshiaki, Muramatsu Toshihide, Ojima Hidenori, Sukeda Aoi, Sugiyama Yuko, Uchida Ryoei, Furukawa Ryo, Kitahara Aya, Sato Toshiro, Kanai Yae, Saito Hidetsugu

    Scientific Reports （SPRINGER NATURE)  8 （ 1 ）  2018.12

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  2045-2322

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    <p>Intrahepatic cholangiocarcinoma (IHCC) is a highly aggressive malignancy with a poor prognosis. It is thought to originate from cholangiocytes, which are the component cells of intrahepatic bile ducts. However, as patients with viral hepatitis often develop IHCC, it has been suggested that transformed hepatocytes may play a role in IHCC development. To investigate whether IHCC cells can be converted to functional hepatocytes, we established organoids derived from human IHCC and cultured them under conditions suitable for hepatocyte differentiation. IHCC organoids after hepatocyte differentiation acquired functions of mature hepatocytes such as albumin secretion, bile acid production and increased CYP3A4 activity. Studies using a mouse model of IHCC indicate that Wnt3a derived from macrophages recruited upon inflammation in the liver may promote the malignant transformation of hepatocytes to IHCC cells. The results of the present study support the recently proposed hypothesis that IHCC cells are derived from hepatocytes.</p>

  • Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis

    Nanki Kosaku, Toshimitsu Kohta, Takano Ai, Fujii Masayuki, Shimokawa Mariko, Ohta Yuki, Matano Mami, Seino Takashi, Nishikori Shingo, Ishikawa Keiko, Kawasaki Kenta, Togasaki Kazuhiro, Takahashi Sirirat, Sukawa Yasutaka, Ishida Hiroki, Sugimoto Shinya, Kawakubo Hirofumi, Kim Jihoon, Kitagawa Yuko, Sekine Shigeki, Koo Bon Kyoung, Kanai Takanori, Sato Toshiro

    Cell （Elsevier)  174 （ 4 ） 856 - 869.e17 2018.08

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0092-8674

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    <p>Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers. Generation and analysis of a human gastric cancer organoid bank reveal insights into molecular features underlying diverse histopathological subtypes and tumor independence from Wnt signals.</p>

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Presentations 【 Display / hide 】

  • 腸管上皮におけるside population細胞の分離と機能解析

    Satou Toshiaki, Matsuzaki Yumi, Kouike Hiroko, Ishii Yasumasa, Hibi Toshifumi, Okano Hideyuki

    第2回日本再生医療学会, 

    2003.03
    , 

    Oral presentation (general)

  • 炎症性腸疾患における腸間膜リンパ節樹状細胞の解析

    Sakuraba Atsushi, Satou Toshirou, Kishi Yuusuke, Hitotsumatsu Osamu, Yoshizawa Shigeo, Inoue Nagamu, Koganei Kazutaka, Fukushima Tsuneo, Ishii Hiromasa, Hibi Toshifumi

    第44回日本消化器病学会, 

    2002.10
    , 

    Other

  • 炎症性腸疾患における腸間膜リンパ節樹状細胞の解析

    Sakuraba atsushi, Satou toshirou, Kishi yuusuke, Hitotsumatsu osamu, Yoshizawa shigeo, Inoue nagamu, Koganei kazutaka, Fukushima, Ishii masahiro, Hibi toshifumi

    第44回日本消化器病学会, 

    2002.10

  • Phenotypic and functional analysis of dendritic cells isolated from the mesenteric lymph nodes of inflammatory dowel disease

    Sakuraba Atsushi, Sato Toshiro, Inoue Nagamu, Koganei Kazutada, Fukushima Tuneo, Ishii Hiromasa, Hibi Toshifumi

    International Congress of Mucosal Immunology, 

    2002.06

  • Phenotypic and Functional Analysis of Dendritic Cells Isolated From The Mesenteric Lymph Nodes of Inflammatory Dowel Disease

    Sakuraba Atsushi, Sato Toshiro, Inoue Nagamu, Koganei Kazutada, Fukushima Tuneo, Ishii Hiromasa, Hibi Toshifumi

    International Congress of Mucosal Immunology, 

    2002.06
    , 

    Oral presentation (invited, special)

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Elucidating a role of niche construction in pathophysiological mechanism of human digestive diseases

    2022.04
    -
    2028.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 基盤研究(S), Principal investigator

  • Grant-in-Aid for Scientific Research (S)

    2017.05
    -
    2022.03

    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, Toshiro Sato, Principal investigator

    　View Summary

    オルガノドライブラリーの構築による消化器疾患形質の統合的理解

    　View Remarks

    課題番号：17H06176

  • Grant-in-Aid for Scientific Research (C)

    2017.04
    -
    2020.03

    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, Coinvestigator(s)

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    消化器がん幹細胞を標的とした創薬スクリーニング

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    課題番号：17K09395
    研究代表者：高野愛(慶應義塾大学 医学部　研究員）
    研究分担者：佐藤俊朗(慶應義塾大学 医学部 准教授)、股野麻未(慶應義塾大学 医学部 研究員)

  • オルガノドライブラリーの構築による消化器疾患形質の統合的理解

    2017.04
    -
    2018.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A) , Principal investigator

  • Grant-in-Aid for Scientific Research (A)

    2017.04
    -
    2017.05

    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, Toshiro Sato, Principal investigator

    　View Summary

    オルガノドライブラリーの構築による消化器疾患形質の統合的理解

    　View Remarks

    課題番号：17H01559

    2017年5月31日基盤研究(S)採択による重複制限のため廃止。

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Awards 【 Display / hide 】

  • 日本消化器病学会研究助成賞

    2011, The Japanese Society of Gastroenterology

  • 慶應義塾大学医学部三四会　三四会奨励賞

    2011, Keio University School of Medicine, Sanshikai

  • 第19回浜名湖シンポジウム　最優秀演題賞

    2011

  • 井上リサーチアウォード

    2012, 公益財団法人井上科学振興財団, 大腸の癌化における必須遺伝子変異の同定

  • 文部科学大臣表彰　若手科学者賞

    2012, 文部科学省, 消化管上皮幹細胞の新規培養法を用いた自己複製機構の研究

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Courses Taught 【 Display / hide 】

  • ONCOLOGY: SEMINAR

    2024

  • ONCOLOGY: PRACTICE

    2024

  • METABOLOMIC SYSTEMS BIOLOGY

    2024

  • MEDICAL CHEMISTRY

    2024

  • MEDICAL BIOCHEMISTRY: SEMINAR

    2024

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Memberships in Academic Societies 【 Display / hide 】

  • The Japanese Society of Gastroenterology

    　

  • The Japanese Society for Regenerative Medicine

    　

  • The Molecular Biology Society of Japan

    　

  • The Japanese Society of Internal Medicine

    　

  • Japanese Cancer Association

    　

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