Molecular mechanisms underlying differentiation of intestinal M cells

• Project/Area Number: 16K08457
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Hokkaido University
• Principal Investigator: Kimura Shunsuke 北海道大学, 医学研究院, 助教 (40444525)
• Research Collaborator: KOBAYASHI nobuhide
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: M細胞 / パイエル板 / Sox8 / IgA / 腸管免疫 / 離乳期 / 粘膜免疫 / 細胞・組織 / 上皮組織

Outline of Final Research Achievements

Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. Sox8 directly binds the promoter region of Gp2 to increase Gp2 expression, which is the hallmark of functionally mature M cells. Furthermore, genetic deletion of Sox8 causes a marked decrease in the number of mature M cells, resulting in reduced antigen uptake in Peyer's patches. Consequently, juvenile Sox8-deficient mice showed attenuated germinal center reactions and antigen-specific IgA responses. These findings indicate that Sox8 plays an essential role in the development of M cells to establish mucosal immune responses.

Academic Significance and Societal Importance of the Research Achievements

M細胞分化を制御する機構には不明な点が多かった。本研究によってSox8がM細胞の機能的な成熟に関与していることが明らかになった。Sox8によって制御される分子の解析を今後続けていくことで、M細胞がどのようにして抗原取り込み能を獲得していくかが明らかになると期待できる。Sox8欠損マウスでは特に離乳後のIgA抗体産生能力が低下していた。これは生後の免疫を獲得するために必要であることから、今後の乳幼児医療に有用な知見となる。

Research Products

• [Journal Article] Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice (2019)
  • Author(s): Kimura Shunsuke、Kobayashi Nobuhide、Nakamura Yutaka、Kanaya Takashi、Takahashi Daisuke、Fujiki Ryoji、Mutoh Mami、Obata Yuuki、Iwanaga Toshihiko、Nakagawa Tomoo、Kato Naoya、Sato Shintaro、Kaisho Tsuneyasu、Ohno Hiroshi、Hase Koji
  • Journal Title: The Journal of Experimental Medicine Volume: 216 Issue: 4 Pages: 831-846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal Lymphatic Endothelial Cells Produce R-Spondin3 (2018)
  • Author(s): Ogasawara Reiki、Hashimoto Daigo、Kimura Shunsuke、Hayase Eiko、Ara Takahide、Takahashi Shuichiro、Ohigashi Hiroyuki、Yoshioka Kosuke、Tateno Takahiro、Yokoyama Emi、Ebata Ko、Kondo Takeshi、Sugita Junichi、Onozawa Masahiro、Iwanaga Toshihiko、Teshima Takanori
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41598-018-29100-7
  • Peer Reviewed / Open Access
• [Journal Article] M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance (2018)
  • Author(s): Yutaka Nakamura, Shunsuke Kimura, Koji Hase
  • Journal Title: Inflammation and Regeneration Volume: 38 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s41232-018-0072-y
  • Peer Reviewed / Open Access
• [Journal Article] Histochemical characteristics of regressing vessels in the hyaloid vascular system of neonatal mice: novel implication for vascular atrophy (2018)
  • Author(s): Kishimoto A, Kimura S, Nio-Kobayashi J, Takahashi-Iwanaga H, Park AM, Iwanaga T
  • Journal Title: Exp Eye Res Volume: 未定 Pages: 1-9
  • DOI: 10.1016/j.exer.2018.03.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling. (2018)
  • Author(s): Kanaya T, Sakakibara S, Jinnohara T, Hachisuka M, Tachibana N, Hidano S, Kobayashi T, Kimura S, Iwanaga T, Nakagawa T, Katsuno T, Kato N, Akiyama T, Sato T, Williams IR, Ohno H.
  • Journal Title: J Exp Med. Volume: 5;215(2) Issue: 2 Pages: 501-519
  • DOI: 10.1084/jem.20160659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular insights into the mechanisms of M-cell differentiation and transcytosis in the mucosa-associated lymphoid tissues (2018)
  • Author(s): Kimura S.
  • Journal Title: Anat Sci Int. Volume: 93 Issue: 1 Pages: 23-34
  • DOI: 10.1007/s12565-017-0418-6
  • Peer Reviewed
• [Journal Article] Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions. (2017)
  • Author(s): Ariazi J, Benowitz A, De Biasi V, Den Boer ML, Cherqui S, Cui H, Douillet N, Eugenin EA, Favre D, Goodman S, Gousset K, Hanein D, Israel DI, Kimura S, Kirkpatrick RB, Kuhn N, Jeong C, Lou E, Mailliard R, Maio S, Okafo G, Osswald M, Pasquier J, Polak R, Pradel G, de Rooij B, Schaeffer P, et al
  • Journal Title: Front Mol Neurosci. Volume: 10 Pages: 333-333
  • DOI: 10.3389/fnmol.2017.00333
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced gap junction intercellular communication inhibits catabolic and pro-inflammatory responses in tenocytes against heat stress. (2017)
  • Author(s): Maeda E, Kimura S, Yamada M, Tashiro M, and Ohashi T
  • Journal Title: J Cell Commun. Signal. Volume: 11 Issue: 4 Pages: 369-380
  • DOI: 10.1007/s12079-017-0397-3
  • Peer Reviewed
• [Journal Article] Intrarenal signaling mediated by CCK plays a role in salt intake-induced natriuresis (2017)
  • Author(s): Takahashi-Iwanaga H, Kimura S, Konno K, Watanabe M, and Iwanaga T,
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 印刷中 Issue: 1 Pages: F20-F29
  • DOI: 10.1152/ajprenal.00539.2016
  • Peer Reviewed
• [Journal Article] Macrophage ubiquitin-specific protease 2 modifies insulin sensitivity in obese mice. (2017)
  • Author(s): Saito N, Kimura S, Miyamoto T, Fukushima S, Amagasa M, Shimamoto Y, Nishioka C, Okamoto S, Toda C, Washio K, Asano A, Miyoshi I, Takahashi E, Kitamura H.
  • Journal Title: Biochem Biophys Rep. Volume: 9 Pages: 322-329
  • DOI: 10.1016/j.bbrep.2017.01.009
  • Peer Reviewed / Open Access
• [Journal Article] <b>The broad distribution of GP2 in mucous glands and secretory pr</b><b>oducts </b> (2016)
  • Author(s): Kimura S, Nio-Kobayashi J, Kishimoto A, Iwanaga T
  • Journal Title: Biomedical Research Volume: 37 Issue: 6 Pages: 351-358
  • DOI: 10.2220/biomedres.37.351
  • NAID: 130005252684
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] <b>Diversity of the intestinal microbiota differently affects non-neuronal and atropine-sensitive ileal contractile responses to short-chain fatty acids in mic</b><b>e </b> (2016)
  • Author(s): Yajima M, Karaki SI, Tsuruta T, Kimura S, Nio-Kobayashi J, Kuwahara A, Yajima T
  • Journal Title: Biomedical Research Volume: 37 Issue: 5 Pages: 319-328
  • DOI: 10.2220/biomedres.37.319
  • NAID: 130005433002
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] Zinc transporter SLC39A7/ZIP7 promotes intestinal epithelial self-renewal by resolving ER stress. (2016)
  • Author(s): Ohashi, W., Kimura, S., Iwanaga, T., Furusawa, Y., Irie, T., Izumi, H., Watanabe, T., Hijikata, A., Hara, T., Ohara, O., Koseki, H., Sato, T., Robine, S., Mori, H., Hattori, Y., Watarai, H., Mishima, K., Ohno, H., Hase, K., Fukada, T.
  • Journal Title: PLoS Genetics Volume: 12 Issue: 10 Pages: e1006349-e1006349
  • DOI: 10.1371/journal.pgen.1006349
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct Roles for the N- and C-terminal Regions of M-Sec in Plasma Membrane Deformation during Tunneling Nanotube Formation. (2016)
  • Author(s): Kimura S, Yamashita M, Yamakami-Kimura M, Sato Y, Yamagata A, Kobashigawa Y, Inagaki F, Amada T, Hase K, Iwanaga T, Ohno H, Fukai S.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 33548-33548
  • DOI: 10.1038/srep33548
  • NAID: 120005855947
  • Peer Reviewed / Open Access
• [Presentation] Sox8は腸管上皮M細胞の分化に必須であり離乳直後の腸管IgA産生に寄与する (2019)
  • Author(s): 小林伸英、木村俊介、中村有孝、岩永敏彦、長谷耕二
  • Organizer: 第4回 日本骨免疫学会ウインターセミナー
• [Presentation] RANKL-OPGバランスによる腸管免疫系の制御 (2019)
  • Author(s): 木村俊介、中村有孝、小林伸英、武藤麻未、岩永ひろみ、岩永敏彦、 長谷耕二
  • Organizer: 第4回 日本骨免疫学会ウインターセミナー
• [Presentation] マウスSox8は腸管M細胞の成熟に必須であり、離乳後IgA産生の構築に関与する (2019)
  • Author(s): 木村俊介、小林伸英、中村有孝、武藤麻未、岩永敏彦、長谷耕二
  • Organizer: 第124回日本解剖学会総会・全国学術集会
• [Presentation] 卵巣摘出マウスにおける抗RANKL抗体および抗Sema4d抗体の顎堤吸収抑制効果の検証 (2019)
  • Author(s): 久本 芽璃、木村俊介、岩田航、小林純子、岩永俊彦、横山敦郎
  • Organizer: 第124回日本解剖学会総会全国学術集会
• [Presentation] Sox8 is essential for the differentiation of M cellsand antigen-specific IgA response (2018)
  • Author(s): Nobuhide Kobayashi, Shunsuke Kimura, Yutaka Nakamura,Takashi Kanaya, Tsuneyasu Kaisho, Hiroshi Ohno, Koji Hase
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Osteoprotegerin-dependent M-cell self-regulation balances gut infection and immunity (2018)
  • Author(s): Shunsuke Kimura, Yutaka Nakamura, Nobuhide Kobayashi, Katsuyuki Shiroguchi, Shintaro Sato, Tsuneyasu Kaisho, Koji Hase
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 卵巣摘出による骨粗鬆症モデルマウスでは抜歯窩の治癒が遅延し、顎堤吸収が長期間継続する (2018)
  • Author(s): 久本 芽璃、木村俊介、岩田航、小林純子、岩永俊彦、横山敦郎
  • Organizer: 第４回日本骨免疫学会
• [Presentation] RANKL-OPGバランスによる濾胞上皮M細胞数の調節と腸管免疫系の制御 (2018)
  • Author(s): 木村 俊介、中村 有孝、小林 伸英、武藤 麻未、岩永 敏彦、長谷 耕二
  • Organizer: 第３回日本免疫学会ウインターセミナー
• [Presentation] 呼吸上皮におけるMicrofold細胞の性状解析とその基礎研究への応用 (2018)
  • Author(s): 木村 俊介、武藤 麻未、岩永 敏彦
  • Organizer: 第123回日本解剖学会総会・全国学術総会
• [Presentation] RANKL-OPGバランスによる腸管上皮M細胞の分化制御機構 (2017)
  • Author(s): 木村俊介、武藤麻未、岩永敏彦
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎大学坂本キャンパス（長崎県・長崎市）
  • Year and Date: 2017-03-28
• [Presentation] 特殊粘膜上皮M細胞の体内分布およびRANKLによるマウス気管・気管支上皮からのM細胞分化誘導 (2017)
  • Author(s): 武藤 麻未、木村 俊介、岩永 敏彦、飯田 順一郎
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎大学坂本キャンパス（長崎県・長崎市）
  • Year and Date: 2017-03-28
• [Presentation] RANKL-RANKシグナルによる腸上皮特殊細胞M細胞の分化制御 (2017)
  • Author(s): 木村俊介、武藤麻未、岩永敏彦
  • Organizer: 第2回日本骨免疫学会ウインターセミナー
  • Place of Presentation: ホテルマロウド軽井沢（長野県・軽井沢市）
  • Year and Date: 2017-01-26
• [Presentation] パイエル板M細胞の成熟過程の可視化 (2017)
  • Author(s): 木村 俊介、武藤 麻未、岩永 敏彦
  • Organizer: 日本顕微鏡学会第７３回学術講演会
• [Presentation] マウス卵巣摘出モデルは抜歯窩修復後の顎堤過吸収を引き起こす (2017)
  • Author(s): 久本 芽璃、木村 俊介、小林 純子、岩田 航、武藤 麻未、岩永 敏彦、横山 敦郎
  • Organizer: 第3回日本骨免疫学会
• [Presentation] 抜歯後の顎骨骨代謝機構の解明を目的としたマウス抜歯モデルの作製. (2017)
  • Author(s): 久本芽璃、木村俊介、岩田航、後藤まりえ、横山敦郎.
  • Organizer: 日本補綴歯科学会第126回学術大会
• [Presentation] 抜歯後の骨代謝機構を解明するための顎堤吸収モデルの構築 (2017)
  • Author(s): 久本芽璃、木村俊介、岩田航、中村祐介、杉山孝博、小林純子、岩永敏彦、横山敦郎
  • Organizer: 第122回 日本解剖学会総会・全国学術集
  • Place of Presentation: 長崎大学坂本キャンパス（長崎県・長崎市）
• [Presentation] Osteoprotegerin regulates the differentiation of Peyer’s patch M cell. (2016)
  • Author(s): Shunsuke Kimura, Mami Mutoh, and Toshihiko Iwanaga
  • Organizer: 10th European Mucosal Immunology Group Meeting,
  • Place of Presentation: コペンハーゲン（デンマーク）
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] RANKL regulates microfold cells in the pseudostratified epithelium lining the trachea of mouse (2016)
  • Author(s): Mami Mutoh, Shunsuke Kimura, Hiromi Takahashi-Iwanaga, Toshihiko Iwanaga, and Junichiro Iida
  • Organizer: The 49th Annual Scientific Congress, Korean Association of Orthodontists
  • Place of Presentation: ソウル市（韓国）
  • Year and Date: 2016-10-07
  • Int'l Joint Research
• [Presentation] Molecular mechanisms of plasma membrane deformation by M-Sec during TNT formation (2016)
  • Author(s): Shunsuke Kimura
  • Organizer: GSK meeting Tunneling Nanotubes (TNTs): Cell-to-Cell Social Networking in Disease Conference
  • Place of Presentation: ペンシルバニア（アメリカ）
  • Year and Date: 2016-09-22
  • Int'l Joint Research / Invited
• [Presentation] Receptor activator of NFκB ligand (RANKL)によるマウス気管・気管支上皮からのM細胞分化誘導 (2016)
  • Author(s): 武藤 麻未、木村 俊介、岩永 敏彦、飯田 順一郎
  • Organizer: 第58回歯科基礎医学会学術大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2016-08-24
• [Presentation] Osteoprotegerinによる腸管上皮M細胞の分化抑制機構とその意義 (2016)
  • Author(s): 木村俊介、武藤麻未、岩永敏彦
  • Organizer: 第58回歯科基礎医学会学術大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
• [Presentation] 抜歯後の顎骨再生機構の解析を目的とした動物実験モデルの開発 (2016)
  • Author(s): 久本芽璃、木村俊介、岩田航、岩永敏彦、横山敦郎
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
• [Book] マウス組織アトラス (2018)
  • Author(s): 岩永 敏彦, 小林 純子, 木村 俊介
  • Total Pages: 168
  • Publisher: 医学書院
  • ISBN: 9784260034333
• [Book] 新編カラーアトラス組織・細胞学 (2017)
  • Author(s): 岩永 敏彦, 木村 俊介, 小林 純子
  • Total Pages: 412
  • Publisher: 医歯薬出版
  • ISBN: 4263458052
• [Remarks] 離乳期における抗体の空白期間を埋めるしくみを解明
  • URL: https://www.hokudai.ac.jp/news/190326_pr.pdf
• [Remarks] Research Press Release
  • URL: https://www.global.hokudai.ac.jp/blog/identifying-a-key-player-in-gut-defense-development/
• [Remarks] 離れた細胞間の物質輸送やシグナル伝達を担う 脂質膜ナノチューブの形成を誘導する仕組み
  • URL: https://www.hokudai.ac.jp/news/160914_nanotube_pr.pdf