Elucidating the mechanism of hematopoietic stem cell development and maturation by using a novel reporter mouse

• Project/Area Number: 17K09958
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kumamoto University
• Principal Investigator: Yokomizo Tomomasa 熊本大学, 国際先端医学研究機構, 特定事業研究員 (80590314)
• 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 / 発生 / 血液 / 発生・分化 / 移植・再生医療

Outline of Final Research Achievements

The aim of this study is to understand how hematopoietic stem cells (HSCs) are generated during mouse development. Especially we focused on how stemness are obtained after the specification of hematopoietic cells. Using the Hlf-tdTomato reporter mouse and Hlf-CreERT2 tracer mouse, we found that Hlf marks the developmental pathway for hematopoietic stem cells. Moreover, through the gene expression analysis of Hlf+ cells, we identified candidate HSC-specifying genes. These results could be applied for developing a new culture system for in vitro HSC induction.

Academic Significance and Societal Importance of the Research Achievements

近年、iPS細胞から様々な種類の細胞の誘導が試みられており、疾患治療・再生医療への応用が期待されている。血液細胞への分化誘導の研究も盛んにおこなわれており、現在までに多種の血液細胞の試験管内誘導が可能となっている。しかしながら、最も応用範囲が広いと思われる造血幹細胞の誘導については、いまだ成功の報告はない。誘導が成功しない理由として、生体内での造血幹細胞の発生メカニズムの詳細が分かっていないことで、生体を模倣した培養系を構築することができない点が指摘されている。本研究は造血幹細胞の発生メカニズムの一端を明らかにしたものであり、造血幹細胞の誘導法開発に向けての有用な情報を与えるものと考えている。

Research Products

• [Int'l Joint Research] University Hospital Zurich(スイス)
• [Int'l Joint Research] University Hospital Zurich(スイス)
• [Int'l Joint Research] University Hospital Zurich(Switzerland)
• [Journal Article] Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors., (2019)
  • Author(s): Tomomasa Yokomizo, Naoki Watanabe, Terumasa Umemoto, Junichi Matsuo, Ryota Harai, Yoshihiko Kihara, Eri Nakamura, Norihiro Tada, Tomohiko Sato, Tomoiku Takaku, Akihiko Shimono, Hitoshi Takizawa, Naomi Nakagata, Seiichi Mori, Mineo Kurokawa, Daniel Tenen, Motomi Osato, Toshio Suda, and Norio Komatsu.
  • Journal Title: J Exp Med Volume: 216 Issue: 7 Pages: 1599-1614
  • DOI: 10.1084/jem.20181399
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Fate tracing of Hlf+ hematopoietic clusters in the developing mouse embryo (2019)
  • Author(s): Tomomasa Yokomizo, Takako Ideue, Mineo Kurokawa, Motomi Osato, Toshio Suda
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Hlf expression marks the developmental pathway for hematopoietic stem cells but not for erythroid-myeloid progenitors (2018)
  • Author(s): Tomomasa Yokomizo, Naoki Watanabe, Terumasa Umemoto, Tomoiku Takaku, Mohamed Gaber, Seiichi Mori, Mineo Kurokawa, Daniel G Tenen, Toshio Suda, Motomi Osato, Norio Komatsu
  • Organizer: 第16回幹細胞シンポジウム
• [Presentation] Evi-1/Hlf axis regulates HSC maturation in the mouse embryo (2018)
  • Author(s): Tomomasa Yokomizo, Naoki Watanabe, Terumasa Umemoto, Tomoiku Takaku, Toshio Suda, Mineo Kurokawa, Norio Komatsu, Motomi Osato
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Hlf expression marks the developmental pathway for hematopoietic stem cells but not for erythroid-myeloid progenitors (2018)
  • Author(s): Tomomasa Yokomizo, Seiichi Mori, Mineo Kurokawa, Motomi Osato, Norio Komatsu
  • Organizer: 第77回日本癌学会学術集会
• [Presentation] Development of HSC-dependent and independent lineages in the mouse embryo (2017)
  • Author(s): Tomomasa Yokomizo, Naoki Watanabe, Tomoiku Takaku, Seiichi Mori, Motomi Osato and Norio Komatsu
  • Organizer: 第15回幹細胞シンポジウム
• [Presentation] Developmental origins of HSC-dependent and independent lineages in the mouse embryo (2017)
  • Author(s): Tomomasa Yokomizo, Naoki Watanabe, Tomoiku Takaku, Seiichi Mori, Motomi Osato and Norio Komatsu
  • Organizer: 第７９回日本血液学会学術集会
• [Presentation] Hlf expression marks developmental pathway for hematopoietic stem cells, but not for erythroid-myeloid progenitors (2017)
  • Author(s): Tomomasa Yokomizo, Naoki Watanabe, Terumasa Umemoto, Tomoiku Takaku, Seiichi Mori, Mineo Kurokawa, Toshio Suda, Motomi Osato and Norio Komatsu
  • Organizer: 21st international Runx conference
  • Int'l Joint Research