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New therapeutic strategy for periodontal disease targeting exosomal miRNA derived from GMSCs.

Research Project

Project/Area Number 20H03865
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 57030:Conservative dentistry-related
Research InstitutionKyushu University

Principal Investigator

Fukuda Takao  九州大学, 大学病院, 講師 (80507781)

Co-Investigator(Kenkyū-buntansha) 武富 孝治  久留米大学, 医学部, 准教授 (10553290)
新城 尊徳  九州大学, 歯学研究院, 助教 (20711394)
讃井 彰一  九州大学, 大学病院, 講師 (70507780)
西村 英紀  九州大学, 歯学研究院, 教授 (80208222)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywords歯肉幹細胞 / エクソソーム / M2マクロファージ / CD73 / miR-1260b / ERストレス / miRNA / 歯周炎
Outline of Research at the Start

幹細胞による疾病治療効果には、幹細胞から分泌されるエクソソームと呼ばれる細胞分泌小胞が中心的役割を果たしており、エクソソームに内包されるmiRNAが損傷組織の遺伝子発現を制御することで治癒を促進することが明らかにされつつある。申請者らは歯肉幹細胞が分泌するエクソソームの有する著明な抗炎症・創傷治癒促進効果を発見したが、その詳細な分子基盤は不明である。
本研究は、歯肉幹細胞由来エクソソームmiRNAを新たな核酸創薬ターゲットとした新規歯周治療の分子基盤を確立することで、最小限の幹細胞から歯周病の炎症の収束・組織リモデリング・再生シグナルを効果的に誘導する革新的歯周治療法の確立を目指す。

Outline of Final Research Achievements

Among the somatic mesenchymal stem cells (MSCs),ginvival tissue-derived MSCs (GMSCs) are easily accessible and characterized by their prominent immunomodulatory and exosome productive capacities. In this project, we reviealed that GMSCs-derived exosomal CD73 is critical for M2 macrophage polarization which contribute to anti-iflammation and tissue repair. We further identified that exosomal miR-1260b inhibits periodontal bone loss by targeting ATF6β mediated regulation of ER stress.These findings are of considerable therapeutic significance to understand the cellular and molecular mechanisms of GMSC-derived exosomes in periodontitis.

Academic Significance and Societal Importance of the Research Achievements

間葉系幹細胞による治療効果には、分泌されるエクソソームと呼ばれる細胞外小胞が重要であることが明らかとなりつつある。本研究では、歯科治療で生じた廃棄歯肉からヒト歯肉幹細胞を単離し、そのエクソソームを用いた歯周炎治療のための基盤研究を行った。本研究により、歯肉幹細胞由来エクソソームに含有される分子が、いかなる機序で歯周炎で損傷を受けた組織で抗炎症作用および歯槽骨吸収抑制効果を生じるかを解明した。これらの知見は歯科にとどまらない、幹細胞医療発展への貢献が期待できる。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 2020 Other

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (24 results) (of which Int'l Joint Research: 10 results,  Invited: 3 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Scaffold-free bone-like 3D structure established through osteogenic differentiation from human gingiva-derived stem cells2024

    • Author(s)
      Toyoda Masaaki、Fukuda Takao、Fujimoto Ryota、Kawakami Kentaro、Hayashi Chikako、Nakao Yuki、Watanabe Yukari、Aoki Tsukasa、Shida Miyu、Sanui Terukazu、Taguchi Masahide、Yamamichi Kensuke、Okabe Ayami、Okada Tatsunori、Oka Kyoko、Nakayama Koichi、Nishimura Fusanori、Kajioka Shunichi
    • Journal Title

      Biochemistry and Biophysics Reports

      Volume: 38 Pages: 101656-101656

    • DOI

      10.1016/j.bbrep.2024.101656

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Luteolin Is a Potential Immunomodulating Natural Compound against Pulpal Inflammation2024

    • Author(s)
      Kawakami Kentaro、Fukuda Takao、Toyoda Masaaki、Nakao Yuki、Hayashi Chikako、Watanabe Yukari、Aoki Tsukasa、Shinjo Takanori、Iwashita Misaki、Yamashita Akiko、Shida Miyu、Sanui Terukazu、Uchiumi Takeshi、Nishimura Fusanori
    • Journal Title

      BioMed Research International

      Volume: 2024 Pages: 1-16

    • DOI

      10.1155/2024/8864513

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epithelial-to-mesenchymal transition, inflammation, subsequent collagen production, and reduced proteinase expression cooperatively contribute to cyclosporin-A-induced gingival overgrowth development2023

    • Author(s)
      Imagawa Mio、Shinjo Takanori、Sato Kohei、Kawakami Kentaro、Zeze Tatsuro、Nishimura Yuki、Toyoda Masaaki、Chen Shuang、Ryo Naoaki、Ahmed Al-kafee、Iwashita Misaki、Yamashita Akiko、Fukuda Takao、Sanui Terukazu、Nishimura Fusanori
    • Journal Title

      Frontiers in Physiology

      Volume: 14 Pages: 01-16

    • DOI

      10.3389/fphys.2023.1298813

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Case of a Dentigerous Cyst in the Maxillary Sinus Treated Preoperatively With Vascular Embolization to Avoid Intraoperative Abnormal Bleeding2023

    • Author(s)
      Taketomi Takaharu、Fukuda Takao、Takeshita Go、Sanui Terukazu
    • Journal Title

      Cureus

      Volume: 15(12)

    • DOI

      10.7759/cureus.50228

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] miR-582-5p targets Skp1 and regulates NF-κB signaling-mediated inflammation2023

    • Author(s)
      Li Rongzhi、Sano Tomomi、Mizokami Akiko、Fukuda Takao、Shinjo Takanori、Iwashita Misaki、Yamashita Akiko、Sanui Terukazu、Nakatsu Yusuke、Sotomaru Yusuke、Asano Tomoichiro、Kanematsu Takashi、Nishimura Fusanori
    • Journal Title

      Archives of Biochemistry and Biophysics

      Volume: 734 Pages: 109501-109501

    • DOI

      10.1016/j.abb.2022.109501

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a novel therapeutic approach for periodontitis that utilizes GMSCs-derived exosome through induction of M2 macrophage2022

    • Author(s)
      Fukuda Takao
    • Journal Title

      Nihon Shishubyo Gakkai Kaishi (Journal of the Japanese Society of Periodontology)

      Volume: 64 Issue: 4 Pages: 109-115

    • DOI

      10.2329/perio.64.109

    • ISSN
      0385-0110, 1880-408X
    • Year and Date
      2022-12-28
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular vesicles derived from GMSCs stimulated with TNF-α and IFN-α promote M2 macrophage polarization via enhanced CD73 and CD5L expression.2022

    • Author(s)
      Watanabe Y, Fukuda T, Hayashi C, Nakao Y, Toyoda M, Kawakami K, Shinjo T, Iwashita M, Yamato H, Yotsumoto K, Taketomi T, Uchiumi T, Sanui T, Nishimura F.
    • Journal Title

      Sci Rep

      Volume: 12(1) Issue: 1 Pages: 13344-13344

    • DOI

      10.1038/s41598-022-17692-0

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] miR-1260b inhibits periodontal bone loss by targeting ATF6β mediated regulation of ER stress.2022

    • Author(s)
      Hayashi C, Fukuda T, Kawakami K, Toyoda M, Nakao Y, Watanabe Y, Shinjo T, Sano T, Iwashita M, Yotsumoto K, Shida M, Taketomi T, Sanui T, Uchiumi T, Kanematsu T, Nishimura F.
    • Journal Title

      Front Cell Dev Biol

      Volume: 10 Pages: 1061216-1061216

    • DOI

      10.3389/fcell.2022.1061216

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss2021

    • Author(s)
      Nakao Yuki、Fukuda Takao、Zhang Qunzhou、Sanui Terukazu、Shinjo Takanori、Kou Xiaoxing、Chen Chider、Liu Dawei、Watanabe Yukari、Hayashi Chikako、Yamato Hiroaki、Yotsumoto Karen、Tanaka Urara、Taketomi Takaharu、Uchiumi Takeshi、Le Anh D.、Shi Songtao、Nishimura Fusanori
    • Journal Title

      Acta Biomaterialia

      Volume: 122 Pages: 306-324

    • DOI

      10.1016/j.actbio.2020.12.046

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immunomodulatory Role of Exosomes Derived from Gingival Mesenchymal Stem Cells2020

    • Author(s)
      福田 隆男
    • Journal Title

      The Japanese Journal of Conservative Dentistry

      Volume: 63 Issue: 2 Pages: 140-143

    • DOI

      10.11471/shikahozon.63.140

    • NAID

      130007840631

    • ISSN
      0387-2343, 2188-0808
    • Related Report
      2020 Annual Research Report
  • [Presentation] miR-1260b promotes M2 macrophage polarization by targeting NFAT5 and NLRP32024

    • Author(s)
      Chikako Hayashi, Masaaki Toyoda, Kentaro Kawakami, Yuki Nakao, Miyu Shida, Takanori Shinjo, Terukazu Sanui, Takao Fukuda, Fusanori Nishimura
    • Organizer
      2024 IADR/AADOCR/CADR General Session & Exhibition
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fabrication of Gingiva-Derived Stem Cell-Based Scaffold-Free Bone-Like 3D Structures2024

    • Author(s)
      Masaaki Toyoda, Shunichi Kajioka, Takao Fukuda, Kentaro Kawakami, Miyu Shida, Chikako Hayashi, Tsukasa Aoki, Tatsuro Zeze, Yuki Nakao, Terukazu Sanui, Fusanori Nishimura
    • Organizer
      2024 IADR/AADOCR/CADR General Session & Exhibition
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] バイオ3Dプリンターを用いた歯肉幹細胞由来骨様立体構造物の作製方法の確立と骨分化能、石灰化度に関する解析2023

    • Author(s)
      豊田真顕、梶岡俊一、福田隆男、川上賢太郎、信太実有、李金鳳、林千華子、中尾雄紀、讃井彰一、西村英紀
    • Organizer
      第66回秋季日本歯周病学会学術大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ヒト歯肉由来幹細胞を用いて作製した骨様立方構造体の解析2023

    • Author(s)
      豊田真顕、梶岡俊一、福田隆男、藤本亮太、川上賢太郎、信太実有、李金鳳、林千華子、中尾雄紀、讃井彰一、中山功一、西村英紀
    • Organizer
      第9回細胞凝集研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] miR-1260b inhibits periodontal bone loss by targeting ATF6β2022

    • Author(s)
      Hayashi C, Kawakami K, Toyoda M, Watanabe Y, Nakao Y, Yotsumoto K, Yamato H, Shinjo T, Sanui T, Fukuda T, Nishimura F.
    • Organizer
      The 108th Annual Meeting of the American Academy of Periodontology
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fabrication of stem cell-based scaffold-free bone-like 3D structures.2022

    • Author(s)
      Toyoda M, Kajioka S, Fujimoto R, Hayashi C, Kawakami K, Watanabe Y, Nakao Y, Yotsumoto K, Sanui T, Fukuda T, Nakayama K, Nishimura. F.
    • Organizer
      The 108th Annual Meeting of the American Academy of Periodontology
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 歯肉幹細胞由来エクソソームのM2マクロファージ誘導 を介した革新的歯周治療の開2022

    • Author(s)
      福田隆男
    • Organizer
      第65回春季日本歯周病学会学術大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 歯肉幹細胞由来エクソソーム内包miR-1260bによる小胞体ストレス応答制御を介した歯周炎骨吸収抑制効果2022

    • Author(s)
      林千華子、福田隆男、渡邊ゆかり、川上賢太郎、豊田真顕、中尾雄紀、四本かれん、大和寛明、新城尊徳、讃井彰一、西村英紀
    • Organizer
      第65回春季日本歯周病学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] バイオ3Dプリンターを用いた、間葉系幹細胞からの骨様立法構造物作製への挑戦2022

    • Author(s)
      豊田真顕、梶岡俊一 、福田隆男 、渡辺ゆかり 、林千華子 、川上賢太郎 、中尾雄紀、四本かれん 、大和寛明 、讃井彰一 、西村英紀
    • Organizer
      第65回春季日本歯周病学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] TNF-α/IFN-α共刺激した歯肉幹細胞由来エクソソームはCD73とCD5Lを介して抗炎症性M2マクロファージを誘導する2022

    • Author(s)
      渡邊ゆかり、林千華子、川上賢太郎、豊田真顕、中尾雄紀、大和寛明、四本かれん、新城尊徳、岩下未咲、讃井彰一、福田隆男、西村英紀
    • Organizer
      第156回日本歯科保存学会2022年度春季学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ヒト歯髄細胞由来マイクロベジクル含有PKRを標的とした歯髄鎮静薬および歯内・歯周病変モデルの作成に向けて2022

    • Author(s)
      川上賢太郎、渡邊ゆかり、林千華子、豊田真顕、新城尊徳、讃井彰一、福田隆男、西村英紀
    • Organizer
      第156回日本歯科保存学会2022年度春季学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] バイオ3Dプリンターを用いた、間葉系幹細胞からの骨様立法構造物作製への挑戦2022

    • Author(s)
      豊田真顕、梶岡俊一 、川上賢太郎 、林千華子 、渡邊ゆかり 、中尾雄紀 、四本かれん 、讃井彰一 、福田隆男 、西村英紀
    • Organizer
      令和4年度日本歯周病学会九州五大学 日本臨床歯周病学会九州支部合同研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ヒト歯髄細胞由来マイクロベジクル含有PKRを標的とした歯髄鎮静薬および歯内・歯周病変モデルの作成に向けて2022

    • Author(s)
      川上賢太郎、渡邊ゆかり、林千華子、豊田真顕、新城尊徳、讃井彰一、福田隆男、西村英紀 ヒ川上賢太郎、渡邊ゆかり、林千華子、豊田真顕、新城尊徳、讃井彰一、福田隆男、西村英紀
    • Organizer
      第157回日本歯科保存学会2022年度秋季学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 歯肉幹細胞由来エクソソームを応用した歯周炎治療の開発に向けて2022

    • Author(s)
      福田隆男
    • Organizer
      第45回日本分子生物学会 バイオテクノロジーセミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 歯肉幹細胞由来エクソソーム 内包miR-1260bによる小胞体ストレス応答制御を介した抗炎症作用2021

    • Author(s)
      林千華子、福田隆男、渡邊ゆかり、川上賢太郎、豊田真顕、中尾雄紀、四本かれん、大和寛明、新城尊徳、讃井彰一、西村英紀
    • Organizer
      第64回春季日本歯周病学会学術大会(WEB開催)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Exosomes derived from GMSCs stimulated with TNF-α and IFN-α promote M2 macrophage polarization via enhanced CD73 and CD5L expression.2021

    • Author(s)
      Yukari Watanabe, Chikako Hayashi, Kentarou Kawakami, Masaaki Toyoda, Yuki Nakao, Karen Yotsumoto, Hiroaki Yamato, Takanori Shinjyo, Terukazu Sanui, Takao Fukuda, Fusanori Nishimura
    • Organizer
      The 69th Annual Meeting of Japanese Association for Dental Research (Hybrid Meeting)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Exosomal miR-1260b derived from TNF-α-treated hGMSCs inhibits periodontal bone loss by targeting ATF6β-mediated regulation of ER stress.2021

    • Author(s)
      Chikako Hayashi, Takao Fukuda, Yukari Watanabe, Kentaro Kawakami, Masaaki Toyoda, Yuki Nakao, Karen Yotsumoto, Hiroaki Yamato, Takanori Shinjo, Terukazu Sanui, Fusanori Nishimura
    • Organizer
      The 69th Annual Meeting of Japanese Association for Dental Research (Hybrid Meeting)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 歯肉幹細胞由来エクソーム内包miR-1260bによる小胞体ストレス応答制御を介した歯槽骨吸収抑制作用2021

    • Author(s)
      林千華子、福田隆男、渡邊ゆかり、川上賢太郎、豊田真顕、中尾雄紀、四本かれん、大和寛明、新城尊徳、讃井彰一、西村英紀
    • Organizer
      第155回日本歯科保存学会2020年度秋季学術大会(WEB開催)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Exosomal miR-1260b derived from TNF-α-treated hGMSCs inhibits periodontal bone loss by targeting ATF6β-mediated regulation of ER stress.2021

    • Author(s)
      Chikako Hayashi, Takao Fukuda, Yukari Watanabe, Kentaro Kawakami, Masaaki Toyoda, Yuki Nakao, Karen Yotsumoto, Hiroaki Yamato, Takanori Shinjo, Terukazu Sanui, Fusanori Nishimura
    • Organizer
      Kyudai Oral Bioscience & OBT Research Center 5th Joint International Symposium
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Exosomes secreted from TNF-α-preconditioned gingival tissue-derived stem cells s enhance M2 macrophage polarization and inhibit periodontal bone loss2021

    • Author(s)
      Takao Fukuda
    • Organizer
      Kyudai Oral Bioscience & OBT Research Center 5th Joint International Symposium 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Therapeutic potential of exosomes derived from GMSCs in periodontal disease2020

    • Author(s)
      Yuki Nakao, Takao Fukuda, Yukari Watanabe, Chikako Hayashi, Kentaro Kawakami, Masaaki Toyoda, Karen Yotsumoto, Hiroaki Yamato, Takanori Shinjyo ,Urara Tanaka, Terukazu Sanui, Fusanori Nishimura
    • Organizer
      The 106th Annual Meeting of the American Academy of Periodontology in collaboration with the Japanese Society of Periodontology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Exosomes from TNF--treated human gingiva-derived MSCs inhibit periodontal bone loss via miR-1260b-mediated RANKL inhibition2020

    • Author(s)
      Yuki Nakao, Takao Fukuda, Yukari Watanabe, Chikako Hayashi, Kentaro Kawakami, Masaaki Toyoda, Karen Yotsumoto, Hiroaki Yamato, Takanori Shinjyo ,Urara Tanaka, Terukazu Sanui, Fusanori Nishimura
    • Organizer
      The 68th Annual Meeting of Japanese Association for Dental Research
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 歯肉幹細胞由来エクソソームは、miR-1260bによるRANKL阻害により歯槽骨吸収を抑制する2020

    • Author(s)
      中尾雄紀、福田隆男、渡邊ゆかり、林千華子、川上賢太郎、豊田真顕、四本かれん、 大和寛明、新城尊徳、田中麗、讃井彰一、西村英紀
    • Organizer
      第153回日本歯科保存学会2020年度秋季学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 歯肉幹細胞GMSC由来エクソソームによるCD73を介した免疫制御機構2020

    • Author(s)
      渡邊ゆかり、福田隆男、中尾雄紀、林千華子、川上賢太郎、豊田真顕、四本かれん、 大和寛明、讃井彰一、西村英紀
    • Organizer
      第153回日本歯科保存学会2020年度秋季学術会
    • Related Report
      2020 Annual Research Report
  • [Book] 幹細胞由来EV~治療,診断,化粧品への展開~第2回 歯肉幹細胞由来エクソソームを応用した歯周炎治療の開発に向けて2022

    • Author(s)
      福田隆男
    • Total Pages
      28
    • Publisher
      和光純薬時報 巻: 90 号: 4 ページ: 10-11 発行年: 2022年10月15日
    • Related Report
      2022 Annual Research Report
  • [Remarks] 九州大学大学院歯学研究院口腔機能修復学講座歯周病学分野

    • URL

      https://www.dent.kyushu-u.ac.jp/perio/index.html

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report 2021 Annual Research Report 2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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