Analysis of hematopoietic stem cell activation induced by Nrf2 inducers

• Project/Area Number: 15K18999
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: MURAKAMI Shohei 東北大学, 加齢医学研究所, 産学官連携研究員 (20746911)
• Research Collaborator: SUZUKI Takuma 東北大学, 大学院・医学系研究科・血液・免疫病学分野, 大学院生
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Keap1-Nrf2制御系 / 造血幹細胞 / 増殖・分化

Outline of Final Research Achievements

To examine whether a stress-responsive transcription factor, Nrf2, contributes to proliferation of hematopoietic stem cells (HSCs) by its transient activation, we treated mice with an Nrf2 inducer, CDDO-Im, and investigated the effects of transient Nrf2 activation on HSCs. Nrf2 activation induced by CDDO-Im treatment promoted HSC proliferation, but bone marrow transplantation experiment revealed that the proliferative HSCs due to the Nrf2 activation easily undergo differentiation and hardly maintain their stem activity. It turned out that under the culture condition with thrombopoietin (TPO), Nrf2 activation enhanced HSC differentiation into megakaryocyte-like cells. Therefore, Nrf2 activation likely induces proliferation/differentiation of HSCs through enhancing the sensitivity to TPO signaling.

Research Products

• [Journal Article] 血液・免疫細胞および白血病細胞におけるKEAP1-NRF2制御系の役割 (2016)
  • Author(s): 村上昌平、本橋ほづみ
  • Journal Title: 臨床血液 Volume: 57 Pages: 1860-1868
  • NAID: 130005420735
• [Journal Article] NRF2 Is a Key Target for Prevention of Noise-Induced Hearing Loss by Reducing Oxidative Damage of Cochlea (2016)
  • Author(s): Honkura, Y. Matsuo, H. Murakami, S. Sakiyama, M. Mizutari, K. Shiotani, A. Yamamoto, M. Morita, I. Shinomiya, N. Kawase, T. Katori, Y. Motohashi, H.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 19329-19329
  • DOI: 10.1038/srep19329
  • NAID: 130005260938
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of Nrf2 in cell proliferation and differentiation (2015)
  • Author(s): Shohei Murakami and Hozumi Motohashi.
  • Journal Title: Free Radical Biology and Medicine Volume: 88 Pages: 168-178
  • DOI: 10.1016/j.freeradbiomed.2015.06.030
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 造血幹細胞におけるKEAP1-NRF2制御系の機能解析 (2016)
  • Author(s): 村上昌平
  • Organizer: 第89回 日本生化学大会
  • Place of Presentation: 仙台国際センター／東北大学川内北キャンパス（宮城県・仙台）
  • Year and Date: 2016-09-25
• [Presentation] Keap1-Nrf2制御系による造血幹細胞の増殖・老化制御 (2016)
  • Author(s): 村上昌平
  • Organizer: 新学術領域研究 酸素生物学＆ダインイングコード
  • Place of Presentation: 一宮シーサイドオーツカ（千葉県・一宮市）
  • Year and Date: 2016-01-26
• [Presentation] KEAP1-NRF2 system contributes to hematopoietic stem cell senescence (2016)
  • Author(s): 村上昌平
  • Organizer: 老化シンポジウム ～健康長寿をめだした老化研究の最前線～
  • Place of Presentation: 明治安田生命ビルMY PLAZAホール（東京都・千代田区））
• [Presentation] A stress-responsive transcriptional factor NRF2 activates hematopoietic stem cells (2015)
  • Author(s): Shohei Murakami
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA.
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] A stress-responsive transcriptional factor NRF2 activates hematopoietic stem cells (2015)
  • Author(s): Shohei Murakami
  • Organizer: 44th Annual Scientific Meeting of the International Society for Experimental Hematology
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] 造血幹細胞におけるKEAP1-NRF2制御系の機能解析 (2015)
  • Author(s): 村上昌平
  • Organizer: 日本生化学会東北支部 第81回例会・シンポジウム
  • Place of Presentation: 東北大学 さくらホール（宮城県・仙台市）
  • Year and Date: 2015-05-09