Single cell analysis in gut by using multi-photon imaging

• Project/Area Number: 20H03665
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Keio University
• Principal Investigator: SUJINO Tomohisa 慶應義塾大学, 医学部(信濃町), 講師 (40464862)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 炎症性腸疾患 / 制御性T 細胞 / 腸管免疫 / Ahrシグナル / 制御性T細胞

Outline of Research at the Start

正常腸管では炎症を誘発する細胞集団と炎症を押さえ込み、免疫応答を負に制御する細胞集団が存在しており、そのバランスで恒常性が維持されている。制御性T細胞(regulatory T cells; Tregs)は消化管における免疫制御の中心を担う細胞として知られており、その欠損や機能不全は炎症性腸疾患などの発症につながる。Tregsの存在は以前から重要視されているが、実際に腸管の中でいかに作用しているかについては不明な点が多い、新しい技術を利用して１つ１つの細胞が消化管の中でどのような局在を示し、局在規定因子を検討する。

Outline of Final Research Achievements

Using two-photon microscopy, we analyzed the localization and dynamics of regulatory T cells (Treg) in the intestinal mucosa (Sujino T. Science 2016). The localization, dynamics, and regulatory mechanism of Tregs in the suppression of inflammation have been unknown; by combining in vivo cell dynamics analysis technology using two-photon microscopy and single-cell functional analysis technology, we have demonstrated that (Aryl-hydrocarbon receptor) Ahr signaling in the intestinal epithelium alters the localization of Tregs within the intestinal tract. We reported that Ahr signaling in intestinal epithelium contributes to the suppression of inflammation by altering the localization of Tregs in the intestinal tract (Yoshimatsu Y, Sujino T. Cell Rep. 2022).

Academic Significance and Societal Importance of the Research Achievements

これまで炎症性腸疾患の治療薬は炎症惹起細胞の抑制がターゲットであった。近年Ahrリガンドを有する青黛という生薬が副作用の問題が存在するものの炎症性腸疾患に有用であると報告されている。しかしその機序は明らかでなかった。我々の報告で、Ahrリガンドが腸管上皮のAhrシグナルを介することで、腸管内における炎症抑制細胞の位置を変化させることが判明し、その結果炎症を抑制することを見出した。
本研究は、Tregに作用することで腸管炎症抑制効果を発揮することのメカニズムを証明し、さらに、その機序が腸管内での局在をかえるというユニークな機序を介していることを明らかにした。

Research Products

• [Journal Article] Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis (2023)
  • Author(s): Hayashi Yukie、Takabayashi Kaoru、Kato Motohiko、Tojo Anna、Aoki Yasuhiro、Hagihara Yuya、Yoshida Kosuke、Yoshimatsu Yusuke、Kiyohara Hiroki、Sugimoto Shinya、Nanki Kosaku、Mikami Yohei、Sujino Tomohisa、Mutaguchi Makoto、Kawaguchi Takaaki、Hosoe Naoki、Yahagi Naohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Gastrointestinal Endoscopy Volume: 97 Issue: 4 Pages: 759-766.e1
  • DOI: 10.1016/j.gie.2022.11.019
  • Peer Reviewed / Open Access
• [Journal Article] Chronic Enteropathy Associated with <i>Solute Carrier Organic Anion Transporter Family, Member 2A1 (SLCO2A1)</i> with Positive Immunohistochemistry for SLCO2A1 Protein (2022)
  • Author(s): Ariake Chizuru、Hosoe Naoki、Sakurai Hinako、Tojo Anna、Hayashi Yukie、JL Limpias Kamiya Kenji、Sujino Tomohisa、Takabayashi Kaoru、Kosaki Kenjiro、Seki Satowa、Hisamatsu Tadakazu、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Internal Medicine Volume: 61 Issue: 17 Pages: 2607-2611
  • DOI: 10.2169/internalmedicine.8939-21
  • NAID: 130008161632
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-09-01
  • Peer Reviewed
• [Journal Article] Efficacy of Calcineurin Inhibitors for Induction of Remission in Intestinal Beh?et’s Disease (2022)
  • Author(s): Kawaguchi Takaaki、Fukata Masayuki、Omori Teppei、Kiyohara Hiroki、Sugimoto Shinya、Nanki Kosaku、Sujino Tomohisa、Mikami Yohei、Kanai Takanori
  • Journal Title: Crohn's &amp; Colitis 360 Volume: 4 Issue: 3 Pages: 1-10
  • DOI: 10.1093/crocol/otac017
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness and Durability of Ustekinumab Therapy With or Without Immunomodulators for Ulcerative Colitis Patients in Japan (2022)
  • Author(s): Aoki Yasuhiro、Sujino Tomohisa、Kawaguchi Takaaki、Sugimoto Shinya、Shimada Fumie、Yoshimatsu Yusuke、Kiyohara Hiroki、Nanki Kosaku、Mikami Yohei、Takabayashi Kaoru、Hosoe Naoki、Ogata Haruhiko、Iwao Yasushi、Kanai Takanori
  • Journal Title: Crohn's &amp; Colitis 360 Volume: 4 Issue: 2 Pages: 1-10
  • DOI: 10.1093/crocol/otac010
  • Peer Reviewed / Open Access
• [Journal Article] Single-cell transcriptomics of human gut T cells identifies cytotoxic CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells (2022)
  • Author(s): Tanemoto Shun,Sujino Tomohisa,Miyamoto Kentaro,Moody Jonathan,Yoshimatsu Yusuke,Ando Yoshinari,Koya Ikuko,Harada Yosuke,Tojo Anna Okuzawa,Ono Keiko,Hayashi Yukie,Takabayashi Kaoru,Okabayashi Koji,Teratani Toshiaki,Mikami Yohei,Nakamoto Nobuhiro,Hosoe Naoki,Ogata Haruhiko,Hon Chung-Chau,Shin Jay W,Kanai Takanori
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 977117-977117
  • DOI: 10.3389/fimmu.2022.977117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protocol to isolate and enrich mouse splenic naive CD4+ T?cells for in?vitro CD4+CD8αα+ cell induction (2022)
  • Author(s): Harada Yosuke、Miyamoto Kentaro、Sujino Tomohisa
  • Journal Title: STAR Protocols Volume: 3 Issue: 4 Pages: 101728-101728
  • DOI: 10.1016/j.xpro.2022.101728
  • Peer Reviewed / Open Access
• [Journal Article] Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut (2022)
  • Author(s): Yoshimatsu Yusuke、Sujino Tomohisa、Hosoe Naoki、et al.
  • Journal Title: Cell Reports Volume: 39 Issue: 6 Pages: 110773-110773
  • DOI: 10.1016/j.celrep.2022.110773
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes (2022)
  • Author(s): Harada Y, Sujino T, Miyamoto K, Nomura E, Yoshimatsu Y, Tanemoto S, Umeda S, Ono K, Mikami Y, Nakamoto N, Takabayashi K, Hosoe N, Ogata H, Ikenoue T, Hirao A, Kubota Y, Kanai T.
  • Journal Title: iScience Volume: 25 Issue: 4 Pages: 104021-104021
  • DOI: 10.1016/j.isci.2022.104021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Feasibility and Safety of Endoscopic Ischemic Polypectomy and Clinical Outcomes in Patients with Peutz?Jeghers Syndrome (with Video) (2022)
  • Author(s): Limpias Kamiya Kenji J. L.、Hosoe Naoki、Takabayashi Kaoru、Okuzawa Anna、Sakurai Hinako、Hayashi Yukie、Miyanaga Ryoichi、Sujino Tomohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Digestive Diseases and Sciences Volume: - Issue: 1 Pages: 252-258
  • DOI: 10.1007/s10620-022-07477-w
  • Peer Reviewed
• [Journal Article] Epithelium Replacement Contributes to Field Expansion of Squamous Epithelium and Ulcerative Colitis?Associated Neoplasia (2022)
  • Author(s): Sugimoto Shinya、Iwao Yasushi、Shimoda Masayuki、Takabayashi Kaoru、Sato Toshiro、Kanai Takanori、Keio IBD Collaborators
  • Journal Title: Gastroenterology Volume: 162 Issue: 1 Pages: 334-337
  • DOI: 10.1053/j.gastro.2021.09.051
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of necessity for endoscopic balloon dilatation in patients with Crohn's disease-related small bowel stenosis (2021)
  • Author(s): Yukie Hayashi, Kaoru Takabayashi, Naoki Hosoe, Hiroki Kiyohara, Satoshi Kinoshita, Kosaku Nanki, Kayoko Fukuhara, Yohei Mikami, Tomohisa Sujino, Makoto Mutaguchi, Takaaki Kawaguchi, Motohiko Kato, Haruhiko Ogata, Takanori Kanai
  • Journal Title: Ann Med. Volume: 53 Issue: 1 Pages: 2025-2033
  • DOI: 10.1080/07853890.2021.1998597
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characteristics of the Mucosal Surface on Scanning Electron Microscopy in Patients with Remitting Ulcerative Colitis (2021)
  • Author(s): Nomura E, Sujino T, Hosoe N, Yoshimatsu Y, Tanemoto S, Takabayashi K, Mutaguchi M, Shimoda M, Naganuma M, Ogata H, Kanai T.
  • Journal Title: Dig Dis Sci. Volume: - Issue: 9 Pages: 1-6
  • DOI: 10.1007/s10620-020-06609-4
  • Peer Reviewed / Open Access
• [Journal Article] CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells (2021)
  • Author(s): Koda Yuzo、Teratani Toshiaki、Chu Po-Sung、Hagihara Yuya、Mikami Yohei、Harada Yosuke、Tsujikawa Hanako、Miyamoto Kentaro、Suzuki Takahiro、Taniki Nobuhito、Sujino Tomohisa、Sakamoto Michiie、Kanai Takanori、Nakamoto Nobuhiro
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 4474-4474
  • DOI: 10.1038/s41467-021-24734-0
  • Peer Reviewed / Open Access
• [Journal Article] Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program (2021)
  • Author(s): London Mariya、Bilate Angelina M.、Castro Tiago B. R.、Sujino Tomohisa、Mucida Daniel
  • Journal Title: Nature Immunology Volume: 22 Issue: 4 Pages: 449-459
  • DOI: 10.1038/s41590-021-00883-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells (2021)
  • Author(s): Suzuki Masataka、Sujino Tomohisa、Chiba Sayako、Harada Yoichi、Goto Motohito、Takahashi Riichi、Mita Masashi、Hamase Kenji、Kanai Takanori、Ito Mamoru、Waldor Matthew Kaden、Yasui Masato、Sasabe Jumpei
  • Journal Title: Science Advances Volume: 7 Issue: 10
  • DOI: 10.1126/sciadv.abd6480
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Various Endoscopic Features in Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma (2021)
  • Author(s): Aoki Yasuhiro、Sujino Tomohisa、Takabayashi Kaoru、Mutakuchi Makoto、Emoto Katsura、Hosoe Naoki、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Case Reports in Gastroenterology Volume: 1 Issue: 1 Pages: 312-322
  • DOI: 10.1159/000513902
  • Peer Reviewed / Open Access
• [Journal Article] Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn's disease in clinical remission (2021)
  • Author(s): Takabayashi K, Hosoe N, Kato M, Hayashi Y, Nanki K, Fukuhara K, Mikami Y, Mizuno S, Sujino T, Mutaguchi M, Naganuma M, Yahagi N, Ogata H, Kanai T.
  • Journal Title: J Gastroenterol. Volume: 56(1) Issue: 1 Pages: 25-33
  • DOI: 10.1007/s12328-020-01261-x
  • Peer Reviewed
• [Journal Article] Clinical, Endoscopic, and Pathological Characteristics of Immune Checkpoint Inhibitor-Induced Gastroenterocolitis (2021)
  • Author(s): Hayashi Y, Hosoe N, Takabayashi K, Limpias Kamiya KJL, Tsugaru K, Shimozaki K, Hirata K, Fukuhara K, Fukuhara S, Mutaguchi M, Sujino T, Sukawa Y, Hamamoto Y, Naganuma M, Takaishi H, Shimoda M, Ogata H, Kanai T.
  • Journal Title: Dig Dis Sci. Volume: - Pages: 1-6
  • DOI: 10.1007/s10620-020-06441-w
  • Peer Reviewed
• [Journal Article] Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn’s disease in clinical remission (2020)
  • Author(s): Takabayashi Kaoru、Hosoe Naoki、Kato Motohiko、Hayashi Yukie、Nanki Kosaku、Fukuhara Kayoko、Mikami Yohei、Mizuno Shinta、Sujino Tomohisa、Mutaguchi Makoto、Naganuma Makoto、Yahagi Naohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 1 Pages: 25-33
  • DOI: 10.1007/s00535-020-01737-0
  • Peer Reviewed / Open Access
• [Journal Article] The liver-brain-gut neural arc maintains the Treg cell niche in the gut (2020)
  • Author(s): Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Sibata S, Miyamoto K, Ishigame H, Chu Po-Sung, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H, Inoue M, Yada T, Kitagawa Y, Yoshimura A, Tanida M, Tsuda M, Iwasaki Y, Kanai T.
  • Journal Title: Nature Volume: 585 Issue: 7826 Pages: 591-596
  • DOI: 10.1038/s41586-020-2425-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mucosal concentrations of N-acetyl-5-aminosalicylic acid is related to endoscopic activity in ulcerative colitis patients with mesalamine. (2020)
  • Author(s): Fukuda T, Naganuma M, Takabayashi K, Hagihara Y, Tanemoto S, Nomura E, Yoshimatsu Y, Sugimoto S, Nanki K, Mizuno S, Mikami Y, Fukuhara K, Sujino T, Mutaguchi M, Inoue N, Ogata H, Iwao Y, Abe T, Kanai T.
  • Journal Title: J Gastroenterol Hepatol. Volume: 35 Issue: 11 Pages: 1878-1885
  • DOI: 10.1111/jgh.15059
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of Novel Ultrathin Single-Balloon Enteroscopy for Crohn's Disease: A Propensity Score-Matched Study (2019)
  • Author(s): Takabayashi Kaoru、Hosoe Naoki、Kato Motohiko、Hayashi Yukie、Miyanaga Ryoichi、Nanki Kosaku、Fukuhara Kayoko、Mikami Yohei、Mizuno Shinta、Sujino Tomohisa、Mutaguchi Makoto、Naganuma Makoto、Yahagi Naohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Gut and Liver Volume: - Issue: 5 Pages: 1-6
  • DOI: 10.5009/gnl19228
  • Peer Reviewed / Open Access