Establishing a new paradigm of pathogenesis of the diseases through the understanding of stem cell aging

• Project Area: Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
• Project/Area Number: 26115001
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo (2018); Chiba University (2014-2017)
• Principal Investigator: Iwama Atsushi 東京大学, 医科学研究所, 教授 (70244126)
• Co-Investigator(Kenkyū-buntansha): 真田 昌 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 高度診断研究部長 (20529044) ; 田久保 圭誉 国立研究開発法人国立国際医療研究センター, その他部局等, 生体恒常性プロジェクト長 (50502788) ; 波江野 洋 国立研究開発法人国立がん研究センター, 先端医療開発センター, 特任研究員 (70706754)
• Research Collaborator: Nishimura Emi ; Sato Toshiro ; Minamino Toru ; Nabeshima Yoichi ; Suda Toshio ; Hara Eiji ; Ho Anthony
• Project Period (FY): 2014-07-10 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥106,080,000 (Direct Cost: ¥81,600,000、Indirect Cost: ¥24,480,000); Fiscal Year 2018: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2016: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2015: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2014: ¥75,140,000 (Direct Cost: ¥57,800,000、Indirect Cost: ¥17,340,000)
• Keywords: ステムセルエイジング / 幹細胞 / 老化 / 疾患 / 加齢 / エイジング / 総括班 / 幹細胞老化と疾患

Outline of Final Research Achievements

To establish and promote the research area, "Stem Cell Aging”, we organized a committee and conducted the following activities: (1) coordination and evaluation of research, (2) organization of committee meetings, (3) research support for young researchers and organization of workshops for young researcher, (4) technical supports, (5) promotion of international collaboration and international exchanges, (6) outreaches and public relations. Through these activities, we accomplished many projects of stem cell aging and aging-related disorders. Many young PIs successfully promoted themselves. We also succeeded to created a good community for this research field.

Academic Significance and Societal Importance of the Research Achievements

「加齢に伴う疾患は、様々な組織幹細胞における加齢変化をベースに、多様な抗老化システムの破綻によって起こる」との仮説のもと、「ステムセルエイジングが加齢に伴う組織・臓器の機能低下や疾患発症にどのように関与するのか」について体系的に研究を推進した。その結果、多くの幹細胞エイジングの実態とその機序が明らかになるとともに、幹細胞エイジングと疾患の関連についても多くの発見があった。領域内での共同研究も活発に行われ、「ステムセルエイジングと疾患」という学術的基盤とコミュニティーが形成されたと評価している。広報活動も積極的に行い、加齢に関連する社会的ニーズに対応する研究分野として認知されつつある。

Research Products

• [Int'l Joint Research] ルンド大学(スウェーデン)
• [Int'l Joint Research] メルボルン大学(オーストラリア)
• [Int'l Joint Research] Baylor大学(米国)
• [Int'l Joint Research] シンガポール大学(シンガポール)
• [Int'l Joint Research] ハイデルベルグ大学(ドイツ)
• [Int'l Joint Research]
• [Int'l Joint Research] ハイデルベルグ大学(ドイツ)
• [Int'l Joint Research] シンガポール大学(シンガポール)
• [Int'l Joint Research] スタンフォード大学/ミネソタ大学(米国)
• [Int'l Joint Research] ルンド大学(スウェーデン)
• [Int'l Joint Research] 内モンゴル大学(中国)
• [Int'l Joint Research] ハイデルベルグ大学(ドイツ)
• [Int'l Joint Research] シンガポール大学(シンガポール)
• [Int'l Joint Research] スタンフォード大学(米国)
• [Int'l Joint Research] ルンド大学(スウェーデン)
• [Int'l Joint Research] ハイデルベルグ大学(ドイツ)
• [Int'l Joint Research] シンガポール大学(シンガポール)
• [Int'l Joint Research] スタンフォード大学(米国)
• [Int'l Joint Research] ルンド大学(スウェーデン)
• [Journal Article] Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis (2018)
  • Author(s): Nanki Kosaku、Toshimitsu Kohta、Takano Ai、Fujii Masayuki、Takahashi Sirirat、Sukawa Yasutaka、Ishida Hiroki、Sugimoto Shinya、Kawakubo Hirofumi、Kim Jihoon、Kitagawa Yuko、Sekine Shigeki、Koo Bon-Kyoung、Kanai Takanori、Sato Toshiro
  • Journal Title: Cell Volume: 174 Issue: 4 Pages: 856-869
  • DOI: 10.1016/j.cell.2018.07.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome. (2018)
  • Author(s): Tara S, Isshiki Y, Nakajima-Takagi Y, Oshima M, Aoyama K, Tanaka T, Shinoda D, Koide S, Saraya A, Miyagi S, Manabe I, Matsui H, Koseki H, Bardwell VJ, Iwama A.
  • Journal Title: Blood Volume: 132(23) Issue: 23 Pages: 2470-2483
  • DOI: 10.1182/blood-2018-01-827964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression. (2018)
  • Author(s): Seino T, Kawasaki S, Shimokawa M, Tamagawa H, Toshimitsu K, Fujii M, Ohta Y, Matano M, Nanki K, Kawasaki K, Takahashi S, Sugimoto S, Iwasaki E, Takagi J, Itoi T, Kitago M, Kitagawa Y, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 3 Pages: 454-467
  • DOI: 10.1016/j.stem.2017.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress (2018)
  • Author(s): Tadokoro Yuko、Hoshii Takayuki、Yamazaki Satoshi、Eto Koji、Ema Hideo、Kobayashi Masahiko、Ueno Masaya、Ohta Kumiko、Arai Yuriko、Hara Eiji、Harada Kenichi、Oshima Masanobu、Oshima Hiroko、Arai Fumio、Yoshimura Akihiko、Nakauchi Hiromitsu、Hirao Atsushi
  • Journal Title: Cell Stem Cell Volume: 22 Issue: 5 Pages: 713-725
  • DOI: 10.1016/j.stem.2018.04.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation (2018)
  • Author(s): Nagase R, Inoue D, Pastore A, Fujino T, Hou HA, Yamasaki N, Goyama S, Saika M, Kanai A, Sera Y, Horikawa S, Ota Y, Asada S, Hayashi Y, Kawabata KC, Takeda R, Tien HF, Honda H, Abdel-Wahab O, Kitamura T.
  • Journal Title: The Journal of Experimental Medicine Volume: 印刷中 Issue: 6 Pages: 1729-1747
  • DOI: 10.1084/jem.20171151
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reconstruction of the Human Colon Epithelium In Vivo. (2018)
  • Author(s): Sugimoto S, Ohta Y, Fujii M, Matano M, Shimokawa M, Nanki K, Date S, Nishikori S, Nakazato Y, Nakamura T, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 2 Pages: 171-176
  • DOI: 10.1016/j.stem.2017.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies (2017)
  • Author(s): Tanaka Tomoyuki、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Tara Shiro、Oshima Motohiko、Saraya Atsunori、Koide Shuhei、Si Sha、Manabe Ichiro、Sanada Masashi、Nakayama Manabu、Masuko Masayoshi、Sone Hirohito、Koseki Haruhiko、Iwama Atsushi
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2901-2913
  • DOI: 10.1084/jem.20170167
  • Peer Reviewed / Open Access
• [Journal Article] Visualization and Targeting of LGR5+ Human Colon Cancer Stem Cells (2017)
  • Author(s): Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T
  • Journal Title: Nature Volume: 印刷中 Issue: 7653 Pages: 13-14
  • DOI: 10.1038/nature22081
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation and cellular communication (2017)
  • Author(s): Fujiu K, Shibata M, Nakayama Y, Ogata F, Matsumoto S, Noshita K, Iwami S, Nakae S, Komuro I, Nagai R, Manabe I
  • Journal Title: Nature Medicine Volume: 印刷中 Issue: 5 Pages: 611-622
  • DOI: 10.1038/nm.4326
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness. (2017)
  • Author(s): Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, Ahuja AK, Lopes M, Hausmann A, Hardt WD, Gomariz A, Nombela-Arrieta C, Manz MG.
  • Journal Title: Cell Stem Cell Volume: 21 Issue: 2 Pages: 225-240
  • DOI: 10.1016/j.stem.2017.06.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. (2016)
  • Author(s): Sashida G, Wang S, Tomioka T, Oshima M, Kazumasa Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A.
  • Journal Title: J Experimenta l Medicine Volume: 213 Issue: 8 Pages: 1459-1477
  • DOI: 10.1084/jem.20151121
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. (2016)
  • Author(s): Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, and Nishimura EK.
  • Journal Title: Science Volume: 351(6273) Issue: 6273 Pages: 575-575
  • DOI: 10.1126/science.aad4395
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p38α activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling. (2016)
  • Author(s): Karigane D, Kobayashi H, Morikawa T, Ootomo Y, Sakai M, Nagamatsu G, Kubota Y, Goda N, Matsumoto M, Nishimura EK, Soga T, Otsu K, Suematsu M, Okamoto S, Suda T, Takubo K.
  • Journal Title: Cell Stem Cell Volume: 19 Pages: 192-294
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements. (2016)
  • Author(s): Fujii M, Shimokawa M, Date S, Takano A, Matano M, Ohta Y, Nanki K, Kawasaki K, Nakazato Y, Uraoka T, Watanabe T, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell Volume: 18 Issue: 6 Pages: 827-838
  • DOI: 10.1016/j.stem.2016.04.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enhanced thrombopoietin but not G-CSF receptor stimulation induces self-renewing hematopoietic stem cell divisions in vivo. (2016)
  • Author(s): Kovtonyuk LV, Markus G. Manz, Takizawa H.
  • Journal Title: Blood Volume: 127 Issue: 25 Pages: 3175-3179
  • DOI: 10.1182/blood-2015-09-669929
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. (2015)
  • Author(s): Mochizuki-Kashio M, Aoyama K, Sashida G, Oshima M, Tomioka T, Muto T, Wang C, and Iwama A.
  • Journal Title: Blood Volume: 126 Pages: 1172-1183
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING. (2015)
  • Author(s): Kobayashi H, Kobayashi CI, Nakamura-Ishizu A, Karigane D, Haeno H, Yamamoto KN, Sato T, Ohteki T, Hayakawa Y, Barber GN, Kurokawa M, Suda T, and Takubo K.
  • Journal Title: Cell Reports Volume: 111 Issue: 1 Pages: 71-84
  • DOI: 10.1016/j.celrep.2015.02.066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The evolution of tumor metastasis during clonal expansion with alterations in metastasis driver genes (2015)
  • Author(s): Yamamoto KN, Nakamura A, Haeno H.
  • Journal Title: Sci Rep Volume: 30:5 Issue: 1 Pages: 15886-15886
  • DOI: 10.1038/srep15886
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. (2015)
  • Author(s): Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu CO, Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa Y, Okuno Y, Chiba K, Tanaka H, Nagata Y, Katagiri T, Kon A, Sanada M, Scheinberg P, Miyano S, Maciejewski JP, Nakao S, Young NS, Ogawa S.
  • Journal Title: N Engl J Med. Volume: 373 Issue: 1 Pages: 35-47
  • DOI: 10.1056/nejmoa1414799
  • NAID: 120005623244
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] UTX insufficiency in the pathogenesis of multiple myeloma (2019)
  • Author(s): Atsushi Iwama
  • Organizer: 2019 US-Japan Symposium on Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies
  • Int'l Joint Research / Invited
• [Presentation] PRC1.1, a variant polycomb repressive complex 1 in normal and malignant hematopoiesis (2019)
  • Author(s): Atsushi Iwama
  • Organizer: 9th Biennial Workshop on the Clinical Translation of Epigenetics in Cancer Therapy
  • Int'l Joint Research / Invited
• [Presentation] 造血幹細胞の加齢変化を規定するエピゲノム特性 (2018)
  • Author(s): 岩間厚志
  • Organizer: 第65回日本実験動物学会総会
  • Invited
• [Presentation] 造血幹細胞のエイジングと加齢関連腫瘍 (2018)
  • Author(s): 岩間厚志
  • Organizer: 帝京大学アジア国際感染制御研究所創設5周年記念国際シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] PRC1.1, a variant polycomb repressive complex 1 in normal and malignant hematopoiesis (2018)
  • Author(s): Atsushi Iwama
  • Organizer: McCulloch & Till Lecture Award, The 47th Annual Scientific Meeting, International Society for Experimental Hematology
  • Int'l Joint Research / Invited
• [Remarks] ステムセルエイジング領域HP
  • URL: http://www.ims.u-tokyo.ac.jp/molmed/stemcellaging/index.html
• [Remarks] 新学術領域「ステムセルエイジングから解明する疾患原理」
  • URL: http://www.m.chiba-u.ac.jp/class/molmed/stemcellaging/index.html
• [Remarks] 新学術領域研究 ステムセルエイジングから解明する疾患原理
  • URL: http://www.m.chiba-u.ac.jp/class/molmed/stemcellaging/results/index.html
• [Remarks] 本領域「ステムセルエイジングから解明する疾患原理」のホームページ
  • URL: http://www.m.chiba-u.ac.jp/class/molmed/stemcellaging/