Aging and anti-aging mechanisms in niche-hematopoietic stem cell interaction

• Project Area: Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
• Project/Area Number: 26115005
• 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: National Center for Global Health and Medicine
• Principal Investigator: TAKUBO Keiyo 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)
• Co-Investigator(Kenkyū-buntansha): 大谷 直子 大阪市立大学, 大学院医学研究科, 教授 (50275195)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥162,630,000 (Direct Cost: ¥125,100,000、Indirect Cost: ¥37,530,000); Fiscal Year 2018: ¥30,290,000 (Direct Cost: ¥23,300,000、Indirect Cost: ¥6,990,000); Fiscal Year 2017: ¥30,290,000 (Direct Cost: ¥23,300,000、Indirect Cost: ¥6,990,000); Fiscal Year 2016: ¥30,420,000 (Direct Cost: ¥23,400,000、Indirect Cost: ¥7,020,000); Fiscal Year 2015: ¥30,290,000 (Direct Cost: ¥23,300,000、Indirect Cost: ¥6,990,000); Fiscal Year 2014: ¥41,340,000 (Direct Cost: ¥31,800,000、Indirect Cost: ¥9,540,000)
• Keywords: 造血幹細胞 / 幹細胞ニッチ / 幹細胞代謝 / メタボローム解析 / 単一細胞トランスクリプトーム解析 / 低酸素 / ストレス応答 / SASP / in vivoイメージング / メタボロミクス / ニッチ / 老化 / 巨核球 / 感染応答

Outline of Final Research Achievements

We identified transcriptome and cell biological differences among hematopoietic stem cell (HSC) aging and cellular senescence. We also found that megakaryocyte, a differentiated cell originated from HSC, was a niche cell for HSCs. Reanalysis of p38MAPK cascade, a signaling pathway that had been clarified as an inducer for HSC aging, revealed that it also protected HSCs from acute stresses. Finally, we developed a method to maintain quiescent HSCs from aging ex vivo.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、造血幹細胞システムをモデルとした、幹細胞やニッチのエイジングと、細胞老化との異同が示され、臓器レベルの抗老化戦略や加齢関連疾患発症の分子機構の一端が明らかとなった。また、既存の造血幹細胞エイジング関連経路の再評価によって、ストレス関連経路と臓器レベルのエイジングを接続する知見がもたらされた。一方、静止期造血幹細胞の体外培養法は、幹細胞の休眠や静止期性、あるいは細胞の“ポテンシャル”を理解するための基礎的な知見と、研究プラットホームをもたらした。以上の知見は超高齢社会における医学・生物学的問題の理解と科学的な解決につながる基盤的知見たりうるものである。

Research Products

• [Int'l Joint Research] CSI Singapore(シンガポール)
• [Int'l Joint Research] Miami University(米国)
• [Journal Article] Abnormal hematopoiesis and hematopoietic stem cell niche (2017)
  • Author(s): 田久保 圭誉、森川 隆之、小林 央
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 10 Pages: 1844-1850
  • DOI: 10.11406/rinketsu.58.1844
  • NAID: 130006132651
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Use of Imaging Techniques to Illuminate Dynamics of Hematopoietic Stem Cells and Their Niches (2017)
  • Author(s): Morikawa Takayuki、Takubo Keiyo
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 5 Pages: 62-62
  • DOI: 10.3389/fcell.2017.00062
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions (2017)
  • Author(s): Karigane Daiki、Takubo Keiyo
  • Journal Title: International Journal of Hematology Volume: 106 Issue: 1 Pages: 18-26
  • DOI: 10.1007/s12185-017-2261-x
  • Peer Reviewed
• [Journal Article] Quiescence of adult oligodendrocyte precursor cells requires thyroid hormone and hypoxia to activate Runx1. (2017)
  • Author(s): Tokumoto Y, Tamaki S, Kabe Y, Takubo K, Suematsu M
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1019-1019
  • DOI: 10.1038/s41598-017-01023-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 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. (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 Issue: 2 Pages: 192-204
  • DOI: 10.1016/j.stem.2016.05.013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypoxia regulates the hematopoietic stem cell niche. (2016)
  • Author(s): Morikawa T, Takubo K.
  • Journal Title: Pflugers Arch. Volume: 468 Issue: 1 Pages: 13-22
  • DOI: 10.1007/s00424-015-1743-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] How hematopoietic stem/progenitors and their niche sense and respond to infectious stress. (2016)
  • Author(s): Kobayashi H, Suda T, Takubo K.
  • Journal Title: Exp Hematol. Volume: 44 Issue: 2 Pages: 92-100
  • DOI: 10.1016/j.exphem.2015.11.008
  • Peer Reviewed / Int'l Joint Research / 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] CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. (2015)
  • Author(s): Nakamura-Ishizu A, Takubo K, Kobayashi H, Suzuki-Inoue K, Suda T.
  • Journal Title: J Exp Med. Volume: 212 Issue: 12 Pages: 2133-46
  • DOI: 10.1084/jem.20150057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Megakaryocytes are essential for HSC quiescence through the production of thrombopoietin (2014)
  • Author(s): Nakamura-Ishizu A, Takubo K, Fujioka M, Suda T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 454(2) Issue: 2 Pages: 353-7
  • DOI: 10.1016/j.bbrc.2014.10.095
  • Peer Reviewed / Open Access
• [Presentation] Metabolic regulation of hematopoietic stem cell function (2017)
  • Author(s): Keiyo Takubo
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: 浜松アクトシティコングレスセンター
  • Year and Date: 2017-03-29
  • Invited
• [Presentation] Metabolic regulation of hematopoietic stem cells in the bone marrow niche. (2015)
  • Author(s): Takubo K.
  • Organizer: Stem Therapy Seminar series at Lund Stem Cell Center
  • Place of Presentation: Lund, Sweden
  • Year and Date: 2015-06-29
  • Int'l Joint Research / Invited
• [Presentation] Stress response signalingin maintenance ofhematopoietic stem cells (2014)
  • Author(s): Keiyo Takubo
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-01
  • Invited
• [Presentation] Megakaryocyte: a novel niche cell for hematopoietic stem cells (2014)
  • Author(s): Keiyo Takubo
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-16
• [Presentation] Megakaryocyte: a novel niche cell for hematopoietic stem cells (2014)
  • Author(s): Keiyo Takubo
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-27
  • Invited
• [Presentation] 造血幹細胞ニッチによる造血恒常性制御 (2014)
  • Author(s): 田久保 圭誉
  • Organizer: 第13回熊本血液感染免疫フォーラム
  • Place of Presentation: ANAクラウンプラザホテル熊本
  • Year and Date: 2014-09-04
  • Invited
• [Presentation] 造血幹・前駆細胞の解糖系代謝によるストレス造血制御 (2014)
  • Author(s): 田久保 圭誉
  • Organizer: 第2回がんと代謝研究会
  • Place of Presentation: 東京理科大学
  • Year and Date: 2014-07-11
  • Invited
• [Remarks] 国立国際医療研究センター研究所生体恒常性プロジェクト公式ウェブサイト
  • URL: https://takubolab.com/
• [Remarks] 国立国際医療研究センター研究所生体恒常性プロジェクト
  • URL: http://www.rincgm.jp/department/pro/04/
• [Remarks] http://www.rincgm.jp/department/pro/04/
• [Remarks] http://www.rincgm.jp/department/pro/04/