オルガノイドデザインによる臓器創出と移植による全身制御

• Project/Area Number: 22H00472
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Juntendo University (2024); Tokyo Medical and Dental University (2022-2023)
• Principal Investigator: 渡辺 守 順天堂大学, 大学院医学研究科, 特任教授 (10175127)
• Co-Investigator(Kenkyū-buntansha): 油井 史郎 東京医科歯科大学, 統合研究機構, 准教授 (00383886) ; 伊藤 剛 東京医科歯科大学, 大学院医歯学総合研究科, プロジェクト助教 (20733900)
• Project Period (FY): 2022-04-01 – 2027-03-31
• Project Status: Granted (Fiscal Year 2024)
• Budget Amount: ¥41,990,000 (Direct Cost: ¥32,300,000、Indirect Cost: ¥9,690,000); Fiscal Year 2024: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2023: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2022: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: オルガノイドデザイン / ArtDO / 全身制御

Outline of Research at the Start

本課題では、まずオルガノイドをデザインして任意の機能を持たせることができるのかという課題に挑戦する。具体的には、腸上皮オルガノイドをアルブミン分泌細胞などの肝細胞、あるいはインスリン分泌細胞などの膵頭細胞へと誘導する方法を探索する。また、このようにデザインしたオルガノイドを大腸に移植することで、機能性臓器を異所性に作成し、肝不全モデルや糖尿病モデルで治療的な効果を発揮するか否かまでを解析し、新しい再生医療のあり方を検証する。

Outline of Annual Research Achievements

本課題は、申請者が従来取り組んできた炎症性腸疾患の難治性潰瘍を腸上皮幹細胞オルガノイドで被覆し、その完全な治癒を目指す細胞治療を推進する研究を基に、腸から樹立したオルガノイドを自在にデザインし、肝不全・糖尿病などの全身的代謝疾患の治療・予防に有効な新しいデザイン化オルガノイド『ArtDO』(Artificial Designed Organoids)を開発し、それを腸へ移植することで異所性の機能性臓器の個体内での創出を目指すArtDO構想を推進し、全身性代謝異常やホルモンネトワーク異常の是正による代謝疾患の新しい治療措置の樹立を目指す課題である。
研究初年度に当たる2022年度には、腸から樹立したオルガノイドを、肝細胞と親和性の高い吸収上皮系の細胞に誘導する方法を確立した。同時に、吸収上皮細胞から肝細胞への誘導に関して、これをブロックする腸上皮特異的な転写因子の存在も明らかにしている。また現在、腸内分泌細胞に膵臓が有するホルモン分泌能を導入することを目指して、まずは重要な膵内分泌ホルモンであるインスリン分泌機構に着目し、インスリン分泌を制御する責任遺伝子の同定に取り組んでいる。なお、ArtDO-Pancreasにおいては、手術検体、EUS-FNA検体から膵GEP-NENオルガノイドを樹立し、他疾患も合わせて幅広く膵臓オルガノイドバンクを予定通り樹立している。同時にRNAの採取を行いRNAーseqを行う準備も行っている。インスリノーマ由来オルガノイドはインスリンを分泌することを確認済みであり、予定どおり解析に用いる。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

腸上皮細胞を肝細胞に誘導するArtDO-liverにおいても、腸上皮細胞を膵島b細胞へ誘導するArtDO-Pancreasにおいても、研究計画に記載した通りに実験が進捗しており、概ね計画通りに進行している。

Strategy for Future Research Activity

ArtDO-liverにおいては、2022年度に同定した肝細胞への成熟を阻害する、腸らしさを頑強に維持する転写因子を阻害する方法を、主に遺伝子操作で行うよう進めていく。ArtDO-Pancreasにおいては、RNAシーケンスなどの手法で、樹立したバイオバンクの解析を進めていく予定である。

Research Products

• [Journal Article] Apelin expression is downregulated in T cells in a murine model of chronic colitis (2023)
  • Author(s): Yamada D、Kojima Yi、Hosoya A、Suzuki、Watabe T、Inoue T、Tsugawa N、Asakawa T、Yonemoto Y、Onizawa M、Nemoto Y、Oshima S、Shimonaka M、Kuba Ki、Ishida J、Fukamizu A、Penninger JM、Watanabe M、Okamoto R、Nagaishi T
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 647 Pages: 72-79
  • DOI: 10.1016/j.bbrc.2023.01.068
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The cost of inflammatory bowel disease in high-income settings: a Lancet Gastroenterology & Hepatology Commission (2023)
  • Author(s): Burisch Johan、Zhao Mirabella、Greenberg Dan、Melberg Hans O、Watanabe Mamoru、Munkholm Pia et al.
  • Journal Title: The Lancet Gastroenterology & Hepatology Volume: 8 Issue: 5 Pages: 458-492
  • DOI: 10.1016/s2468-1253(23)00003-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Organoids transplantation as a new modality to design epithelial signature to create a membrane-protective sulfomucin-enriched segment (2023)
  • Author(s): Watanabe Satoshi、Ogasawara Nobuhiko、Kobayashi Sakurako、Kirino Sakura、Inoue Masami、Hiraguri Yui、Nagata Sayaka、Shimizu Hiromichi、Ito Go、Mizutani Tomohiro、Nemoto Yasuhiro、Tsuchiya Kiichiro、Okamoto Ryuichi、Watanabe Mamoru、Yui Shiro
  • Journal Title: Journal of Gastroenterology Volume: 58 Issue: 4 Pages: 379-393
  • DOI: 10.1007/s00535-023-01959-y
  • Peer Reviewed
• [Journal Article] Efficacy and safety of filgotinib as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a post-hoc analysis of the phase 2b/3 SELECTION trial (2023)
  • Author(s): Hibi Toshifumi、Motoya Satoshi、Hisamatsu Tadakazu、Hirai Fumihito、Watanabe Kenji、Matsuoka Katsuyoshi、Saruta Masayuki、Kobayashi Taku、Feagan Brian G、Tasset Chantal、Besuyen Robin、Yun Chohee、Crans Gerald、Zhang Jie、Kondo Akira、Watanabe Mamoru
  • Journal Title: Intestinal Research Volume: 21 Issue: 1 Pages: 110-125
  • DOI: 10.5217/ir.2021.00143
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serum Leucine-Rich α2 Glycoprotein: A Novel Biomarker for Transmural Inflammation in Crohn's Disease (2022)
  • Author(s): Kento Takenaka, Yoshio Kitazume, Ami Kawamoto, Toshimitsu Fujii, Yumi Udagawa, Ryosuke Wanatabe, Hiromichi Shimizu, Shuji Hibiya, Masakazu Nagahori, Kazuo Ohtsuka, Hiroyuki Sato, Akihiro Hirakawa, Mamoru Watanabe, Ryuichi Okamoto
  • Journal Title: Am J Gastroenterol. Volume: - Issue: 6 Pages: 1028-1035
  • DOI: 10.14309/ajg.0000000000002127
  • Peer Reviewed
• [Journal Article] Transmural remission characterized by high biologic concentrations demonstrates better prognosis in Crohn's disease (2022)
  • Author(s): Kento Takenaka, Ami Kawamoto, Yoshio Kitazume, Toshimitsu Fujii, Yumi Udagawa, Hiromichi Shimizu, Shuji Hibiya, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe, Ryuichi Okamoto
  • Journal Title: J Crohns Colitis. Volume: - Issue: 6 Pages: 855-862
  • DOI: 10.1093/ecco-jcc/jjac185
  • Peer Reviewed
• [Journal Article] Collagen type I-mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation (2022)
  • Author(s): Kobayashi S, Ogasawara N, Watanabe S, Yoneyama Y, Kirino S, Hiraguri Y, Inoue M, Nagata S, Okamoto-Uchida Y, Kofuji S, Shimizu H, Ito G, Mizutani T, Yamauchi S, Kinugasa Y, Kano Y, Nemoto Y, Watanabe M, Tsuchiya K, Nishina H, Okamoto R, Yui S.
  • Journal Title: Inflammation and Regeneration Volume: 42 Issue: 1 Pages: 49-49
  • DOI: 10.1186/s41232-022-00237-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suspension culture in a rotating bioreactor for efficient generation of human intestinal organoids (2022)
  • Author(s): Takahashi Junichi、Mizutani Tomohiro、Sugihara Hady Yuki、Nagata Sayaka、Kato Shu、Hiraguri Yui、Takeoka Sayaka、Tsuchiya Mao、Kuno Reiko、Kakinuma Sei、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Cell Reports Methods Volume: 2 Issue: 11 Pages: 100337-100337
  • DOI: 10.1016/j.crmeth.2022.100337
  • Peer Reviewed / Open Access
• [Journal Article] Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis. (2022)
  • Author(s): Tamura A, Ito G, Matsuda H, Nibe-Shirakihara Y, Hiraoka Y, Kitagawa S, Hiraguri Y, Nagata S, Aonuma E, Otsubo K, Nemoto Y, Nagaishi T, Watanabe M, Okamoto R, Oshima S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 628 Pages: 147-154
  • DOI: 10.1016/j.bbrc.2022.08.046
  • Peer Reviewed
• [Journal Article] Mucosal healing of small intestinal stricture is associated with improved prognosis post-dilation in Crohn's disease (2022)
  • Author(s): Shuji Hibiya, Kazuo Ohtsuka, Kento Takenaka, Ami Kawamoto, Yusuke Matsuyama, Yumi Udagawa, Maiko Motobayashi, Hiromichi Shimizu, Toshimitsu Fujii, Eiko Saito, Masakazu Nagahori, Ryuichi Okamoto, Mamoru Watanabe
  • Journal Title: BMC Gastroenterol. Volume: 22 Issue: 1 Pages: 218-218
  • DOI: 10.1186/s12876-022-02300-2
  • Peer Reviewed / Open Access
• [Journal Article] Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results. (2022)
  • Author(s): Panes J,Colombel JF,D’Hanes GR,Schreiber S,Panaccione R,Peyrin-Biroulet L,Loftus EV Jr,Danese S,Tanida S,Okuyama Y,Louis E,Armuzzi A,Ferrante M,Vogelsang H,Hibi T,Watanabe M,Lefebve J,Finney-Hayward T,Gonzalez YS,Doan TT,Mostafa NM,Ikeda K,Xie W,Huang B,Petersson J,Kalabic J,Robinson AM,Sandborn WJ
  • Journal Title: Gastroenterology Volume: - Issue: 7 Pages: 1891-1910
  • DOI: 10.1053/j.gastro.2022.02.033
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] AJM300(carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled phase 3 study. (2022)
  • Author(s): Matsuoka K, Watanabe M, Ohmori T, Nakajima K, Ishida T, Ishiguro Y, Kanke K, Kobayashi K, Hirai F, Watanabe K, Mizusawa H, Kishida S, Miura Y, Ohta A, Kajioka T, Hibi T
  • Journal Title: Lancet Gastroenterol Hepatol Volume: - Issue: 7 Pages: 648-657
  • DOI: 10.1016/s2468-1253(22)00022-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nickel particles are present in Crohn's disease tissue and exacerbate intestinal inflammation in IBD susceptible mice. (2022)
  • Author(s): Hiroki Matsuda, Yoichi Nibe-Shirakihara, Akiko Tamura, Emi Aonuma, Satoko Arakawa, Kana Otsubo, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Shigeomi Shimizu, Averil Ma, Mamoru Watanabe, Motohiro Uo, Ryuichi Okamoto, Shigeru Oshima.
  • Journal Title: Biochemical and Biophysical Research Communications. Volume: 592 Pages: 74-80
  • DOI: 10.1016/j.bbrc.2021.12.111
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transplantation of intestinal organoids into a mouse model of colitis (2022)
  • Author(s): Watanabe Satoshi、Kobayashi Sakurako、Ogasawara Nobuhiko、Okamoto Ryuichi、Nakamura Tetsuya、Watanabe Mamoru、Jensen Kim B.、Yui Shiro
  • Journal Title: Nature Protocols Volume: 17 Issue: 3 Pages: 649-671
  • DOI: 10.1038/s41596-021-00658-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Artificial intelligence for endoscopy in inflammatory bowel disease (2022)
  • Author(s): Takenaka Kento、Kawamoto Ami、Okamoto Ryuichi、Watanabe Mamoru、Ohtsuka Kazuo
  • Journal Title: Intestinal Research Volume: 20 Issue: 2 Pages: 165-170
  • DOI: 10.5217/ir.2021.00079
  • Peer Reviewed
• [Journal Article] Deep neural network for video colonoscopy of ulcerative colitis: a cross-sectional study (2022)
  • Author(s): Kento Takenaka, Toshimitsu Fujii, Ami Kawamoto, Kohei Suzuki, Hiromichi Shimizu, Chiaki Maeyashiki, Osamu Yamaji, Maiko Motobayashi, Akira Igarashi, Ryoichi Hanazawa, Shuji Hibiya, Masakazu Nagahori, Eiko Saito, Ryuichi Okamoto, Kazuo Ohtsuka, Mamoru Watanabe
  • Journal Title: Lancet Gastroenterol Hepatol Volume: 7 Issue: 3 Pages: 230-237
  • DOI: 10.1016/s2468-1253(21)00372-1
  • Peer Reviewed / Open Access
• [Journal Article] Activated mucosal-associated invariant T cells have a pathogenic role in a murine model of inflammatory bowel disease. (2022)
  • Author(s): usuke Yasutomi, Asako Chiba, Keiichi Haga, Goh Murayama, Ayako Makiyama, Taiga Kuga, Mamoru Watanabe, Ryuichi Okamoto, Akihito Nagahara, Takashi Nagaishi, Saichiko Miyake.
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology. Volume: 13 Issue: 1 Pages: 81-93
  • DOI: 10.1016/j.jcmgh.2021.08.018
  • Peer Reviewed / Open Access
• [Journal Article] Serum leucine-rich α-2 glycoprotein; a novel biomarker for small bowel mucosal activity in Crohn’s Disease. (2021)
  • Author(s): Kawamoto T, Takenaka K, Hibiya S, Ohtsuka K, Okamoto R, Watanabe M
  • Journal Title: Clin Gastroenterol Hepatol. Volume: 20 Issue: 5 Pages: e1196-e1200
  • DOI: 10.1016/j.cgh.2021.06.036
  • Peer Reviewed
• [Presentation] 半世紀を迎えた難病研究班の現在、過去、未来 (2022)
  • Author(s): 渡辺 守
  • Organizer: 第13回日本炎症性腸疾患学会学術集会（特別企画1）
  • Invited
• [Presentation] 難病医療ネットワークのこれまでと今後 ～レジェンドからのメッセージ～ 消化器難病関連の難病医療ネットワークのこれまでと今後 (2022)
  • Author(s): 渡辺 守
  • Organizer: 日本難病医療ネットワーク学会シンポジウム
  • Invited
• [Presentation] 小腸からヒト全身を繙く時代へ (2022)
  • Author(s): 渡辺 守
  • Organizer: 第60回日本小腸学会学術集会（特別講演）
  • Invited
• [Presentation] Association of Ulcerative Colitis Bowel Urgency Improvement With Clinical Response and Remission. (2022)
  • Author(s): David B. Clemow, Christophe Sapin, Toshifumi Hibi, Marla C. Dubinsky, Severine Vermeire, Stefan Schreiber, Theresa Hunter Gibble, Laurent Peyrin-Biroulet, Mamoru Watanabe, Remo Panaccione
  • Organizer: UEGW2022
  • Int'l Joint Research
• [Presentation] Analysis of molecular characteristics and metastatic mechanism of pancreatic neuroendocrine neoplasms (2022)
  • Author(s): Go Ito, Konrad Aden, Philip Rosenstiel, Mamoru Watanabe et al.
  • Organizer: International Syscid Symposium 2022
  • Int'l Joint Research
• [Presentation] Application of DSS-Grafting Assay to Evaluate the Potential of Cecum Organoids as a Useful Cellular Source for the Treatment of Colitis (2022)
  • Author(s): Satoshi Watanabe, Nobuhiko Ogasawara, Sakurako Kobayashi , Go Ito, Yoshihito Kano, Tomohiro Mizutani, Hiromichi Shimizu , Mamoru Watanabe, Ryuichi Okamoto, Shiro Yui
  • Organizer: DDW2022
  • Int'l Joint Research
• [Presentation] Dissection of inflammatory and regenerative signature of intestinal epithelium via in vitro culture recapitulating the repair process (2022)
  • Author(s): Sakurako Kobayashi, Nobuhiko Ogasawara, Satoshi Watanabe, Go Ito, Yoshihito Kano, Tomohiro Mizutani, Hiromichi Shimizu , Mamoru Watanabe, Ryuichi Okamoto, Shiro Yui
  • Organizer: DDW2022
  • Int'l Joint Research
• [Presentation] Dissection of cancer cell plasticity in a novel defined culture system for human colorectal cancer (2022)
  • Author(s): Nobuhiko Ogasawara, Sakurako Kobayashi, Satoshi Watanabe, Go Ito, Yoshihito Kano, Tomohiro Mizutani, Hiromichi Shimizu , Mamoru Watanabe, Ryuichi Okamoto, Shiro Yui
  • Organizer: DDW2022
  • Int'l Joint Research
• [Presentation] 日本発の経口インテグリン阻害薬がもたらす潰瘍性大腸炎治療の新たな選択肢 (2022)
  • Author(s): 渡辺 守
  • Organizer: 第103回日本消化器内視鏡学会総会セミナー
  • Invited