Establishment and application of mouse and human phagocytes using differentiation reprogram

• Project/Area Number: 15H04717
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kanazawa Medical University (2016-2017); Tokyo Medical and Dental University (2015)
• Principal Investigator: Onai Nobuyuki 金沢医科大学, 医学部, 教授 (50323605)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 樹状細胞 / 前駆細胞 / 転写因子 / 分化 / 単核貪食細胞 / 免疫学 / 単核性貪食細胞 / マクロファージ / 単球 / 分化リプログラム / 貪食細胞 / リプログラム

Outline of Final Research Achievements

Dendritic cells (DCs) are consisted conventional DCs and plasmacytoid DC (pDCs) which have antigen presentation capacity and type-I interferon producing capacity, respectively. In this study, we generate E2-2 reporter mouse which is essential transcription factor for pDC development. Using this mouse, we identified E2-2high and E2-2lo cells in th common DC progenitor (CDPs). E2-2highCDPs develop only pDC in vivo in the spleen, however, in the small intestine, some E2-2highCDPs develop into cDC. This trans-differentiation is mediated by IL-3, IL-5, GM-CSF (all enriched in the gut tissue). In ex vivo cultures with Flt3L+GM-CSF, E2-2highCDPs derived cDCs, but not pDCs, induce Foxp3+ Treg. E2-2 is therefore important in committing pDC differentiation but conversion to cDCs can occur in the intestine and modulate regulatory environment there.

Research Products

• [Journal Article] Flexible fate commitment of E2-2high common DC progenitors implies tuning in tissue microenvironments (2017)
  • Author(s): Onai Nobuyuki、Asano Jumpei、Kurosaki Rumiko、Kuroda Shoko、Ohteki Toshiaki
  • Journal Title: International Immunology Volume: 29 Issue: 10 Pages: 443-456
  • DOI: 10.1093/intimm/dxx058
  • Peer Reviewed
• [Journal Article] Mast cell hyperactivity underpins the development of oxygen-induced retinopathy. (2017)
  • Author(s): Matsuda K, Okamoto N, Kondo M, Arkwright PD, Karasawa K, Ishizaka S, Yokota S, Matsuda A, Jung K, Oida K, Amagai Y, Jang H, Noda E, Kakinuma R, Yasui K, Kaku U, Mori Y, Onai N, Ohteki T, Tanaka A, Matsuda H
  • Journal Title: J. Clin. Invest. Volume: 127 Issue: 11 Pages: 3987-4000
  • DOI: 10.1172/jci89893
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intrinsic autophagy is required for the maintenance of intestinal stem cells and for irradiation-induced intestinal regeneration. (2017)
  • Author(s): Asano J, Sato T, Ichinose S, Kajita M, Onai N, Shimizu S, Ohteki T.
  • Journal Title: Cell reports Volume: 20 Issue: 5 Pages: 1050-1060
  • DOI: 10.1016/j.celrep.2017.07.019
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a human clonogenic progenitor with strict monocyte differentiation potential: A counterpart of mouse cMoPs (2017)
  • Author(s): Kawamura S, Onai N, Miya F, Sato T, Tsunoda T, Kurabayashi K, Yotsumoto S, Kuroda S, Takenaka K, Akashi K, Ohteki T
  • Journal Title: Immunity Volume: 46 Issue: 5 Pages: 835-848
  • DOI: 10.1016/j.immuni.2017.04.019
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a human clonogenic progenitor with strict monocyte differentiation potential - a counterpart of mouse cMoPs. (2017)
  • Author(s): Kawamura S, Onai N, Kurabayashi K, Sato T, Miya F, Tsunoda, T, Yotsumoto S, Kuroda S, Takenaka K, Akashi K, Ohteki T.
  • Journal Title: Immunity Volume: 未定
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cytosine-phosphorothionate- guanine oligodeoxynucleotides exacerbates hemophagocytosis by inducing tumor necrosis factor-α production in mice after bone marrow transplanation. (2016)
  • Author(s): Liu J, Guo YM, Onai N, Ohyagi H, Hirokawa M, Takahashi N, Tagawa H, Ubukawa K, Kobayahi I, Tezuka H, Minamiya Y, Ohteki T, and Sawada K.
  • Journal Title: Biol Blood Marrow Transplant 2015 Volume: 印刷中 Issue: 4 Pages: 627-636
  • DOI: 10.1016/j.bbmt.2015.12.018
  • Peer Reviewed / Open Access
• [Presentation] Identification of Flt3-ligand producing cells by generating Flt3-ligand mCherry reporter mouse. (2017)
  • Author(s): Nobuyuki Onai and Toshiaki Ohteki.
  • Organizer: 5th Annual Meeting of the international Cytokine and Interferon Society.
  • Int'l Joint Research
• [Presentation] Involvement of poly-rC binding proteins in posttranscriptional regulation of Sortilin, the cytokine trafficking mediator. (2017)
  • Author(s): Toshiki Yabe-Wada, Shintaro Matsuba, Kazuya Takeda, Akira Nakamura, Haifeng Shi, Caroline C. Philpott, Nobuyuki Onai.
  • Organizer: 5th Annual Meeting of the international Cytokine and Interferon Society.
  • Int'l Joint Research
• [Presentation] Regulation of pDC development by graded expression of E2-2. (2017)
  • Author(s): Nobuyuki Onai and Toshiaki Ohteki.
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology.
  • Int'l Joint Research
• [Presentation] SLPI negatively regulates LPS-induced eosinophil activation via inhibition of Elk-1 phosphorylation. (2017)
  • Author(s): 4.Shintaro Matsuba, Toshiki Yabe-Wada, Kazuya Takeda, Nobuyuki Onai, Toshiyuki Takai, Akira Nakamura.
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology.
  • Int'l Joint Research
• [Presentation] Regulation of pDC development by graded expression of E2-2. (2017)
  • Author(s): Nobuyuki Onai, Junpei Asano, Shoko Kuroda, and Toshiaki Ohteki.
  • Organizer: 第27回 日本樹状細胞研究会.
• [Book] “Isolation of mouse dendritic cell progenitor and bone marrow progenitor”. Methods Mol. Biol. (2016)
  • Author(s): Onai N & Ohteki T
  • Total Pages: 8
  • Publisher: Human Press, UK
• [Remarks] 金沢医科大学医学部免疫学講座ホームページ
  • URL: http://www.kanazawa-med.ac.jp/~serol/Immunology/Top_Page.html
• [Remarks] 東京医科歯科大学難治疾患研究所生体防御学分野ホームページ
  • URL: http://www.tmd.ac.jp/mri/bre/index.html