Function of Foxp2 in the maintenance of hematopoietic stem cells.

• Project/Area Number: 17K09907
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: Hosokawa Kentaro 九州大学, 医学研究院, 講師 (90569584)
• Co-Investigator(Kenkyū-buntansha): 新井 文用 九州大学, 医学研究院, 教授 (90365403)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 造血幹細胞 / 細胞周期 / Foxp2 / 静止期 / 発生・分化 / 老化

Outline of Final Research Achievements

This study found that Foxp2 was specifically expressed in quiescent hematopoietic stem cells (HSCs), and suggested that Foxp2 negatively regulates the cell cycle of HSCs. Foxp2-deficient mouse-derived HSCs were found to have activation of the cell cycle, activation of several signal pathways observed during proliferation, and enhancement of energy production. On the other hand, HSCs exogenously overexpressing Foxp2 were found to highly express CDK inhibitors and suppress the signal system that promotes proliferation. It was also shown that these cells can withstand the stress of transplantation and maintain long-term bone marrow reconstitution ability.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞が生体において長期に渡って維持されるためには、細胞周期を低速に抑えることが必須であるが、これまでどのようなシグナル系を介して静止期に維持されるのかは不明であった。そこで本研究では、静止期造血幹細胞に特異的なFoxp2を介した維持機構について解析を行い、Foxp2が影響を与えるいくつかのシグナル経路を見出すことができた。さらに、造血幹細胞に対して外因性にFoxp2の発現を高めることで静止期の維持を促進し、幹細胞の活性自体も長期に保持できることが分かった。本研究成果は、幹細胞制御技術の開発において重要な知見となることが考えられ、生体外でのヒト造血幹細胞の遺伝子治療への応用が期待される。

Research Products

• [Journal Article] The role of telomere binding molecules for normal and abnormal hematopoiesis. (2018)
  • Author(s): Hosokawa K, Arai F.
  • Journal Title: Int J Hematol. Volume: 印刷中 Issue: 6 Pages: 646-655
  • DOI: 10.1007/s12185-018-2432-4
  • Peer Reviewed / Open Access
• [Journal Article] The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age (2017)
  • Author(s): Hosokawa Kentaro、MacArthur Ben D.、Ikushima Yoshiko Matsumoto、Toyama Hirofumi、Masuhiro Yoshikazu、Hanazawa Shigemasa、Suda Toshio、Arai Fumio
  • Journal Title: Nature Communications Volume: 8(804) Issue: 1 Pages: 804-818
  • DOI: 10.1038/s41467-017-00935-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional analysis of Protection of Telomeres 1a (Pot1a) in regulation of hematopoietic stem cell aging (2017)
  • Author(s): Hosokawa K, Macarthur BD, Ikushima Y, Toyama H, Masuhiro Y, Hanazawa S, Suda T, Arai F.
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 8 Pages: 942-949
  • DOI: 10.11406/rinketsu.58.942
  • NAID: 130006067976
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] POT1a deficiency in mesenchymal niche cells results in bone marrow failures and skeletal retardation (2018)
  • Author(s): Kentaro Nakashima, Yuya Kunisaki, Kentaro Hosokawa, Shouichi Ohga, Fumio Arai
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Foxp2 is necessary for maintenance of quiescence in hematopoietic stem cells. (2017)
  • Author(s): Kentaro Hosokawa, Saki Morimoto, Yuya Kunisaki, Haruka Imanishi, Tomoko Hyoda, Yasufumi Uehara, and Fumio Arai
  • Organizer: ISEH 46th Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] 造血幹細胞の未分化性維持における転写因子Foxp2の機能解析 (2017)
  • Author(s): Saki Morimoto, Kentaro Hosokawa, Yuya Kunisaki, Haruka Imanishi, Tomoko Hyoda, Yasufumi Uehara, Fumio Arai
  • Organizer: 第79回日本血液学会学術集会