The maintenance of hematopoietic stem cells through tuning TPO response

• Project/Area Number: 19K22641
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Umemoto Terumasa 熊本大学, 国際先端医学研究機構, 特任准教授 (50620225)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 造血幹細胞

Outline of Research at the Start

サイトカイン 「Thrombopoietin (TPO）」は造血幹細胞の増殖・維持・分化を司ることが知られているが、どのようにこれらの機能が制御されているかは未だに不明である。本研究ではTPOシグナルが“エネルギー代謝制御”によって、自己複製分裂誘導用にチューニングされるという仮説のもと、TPOが機能を使い分ける機構を明らかにする共に、未だ確立されていない ex vivo における造血幹細胞の維持・増幅の実現を目指す。

Outline of Final Research Achievements

In this study, we found that the regulation of glucose or glutamine uptake is important to regulate the differentiation of hematopoietic stem cells (HSCs in the presence of Thrombopoietin (TPO）, which have multi-functions in HSCs. In addition, we suggested that HSCs regulate TPO responses through changing chromatin accessibility pattern. In addition of the change of changing chromatin accessibility pattern, Acly-dependent histone acetylation is required to induce the differentiation of HSCs under TPO stimulation. Moreover, the combination between low nutrition and Acly suppression contributes to the maintenance of stem-ness especially within the rapidly divided HSC fraction.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果は、造血幹細胞における「Thrombopoietin (TPO）」の相反する効果が制御されるメカニズムの一端を明らかにした。さらに、幹細胞研究において、「自己複製・分化誘導の選択機構」の解明は古くからの大きな問いであり、本研究の成果は、TPO刺激をモデルとして、その機構の解明に寄与したと考えられる。さらに、TPO刺激と代謝制御が試験管内での造血幹細胞維持に寄与することも見出した。従って、本研究の成果は「造血幹細胞の増幅・維持が可能な培養条件」の開発に寄与すると考えられ、将来的には、骨髄移植療法の質・安全・適応の拡大や、造血幹細胞を用いた遺伝子療法にも大きく貢献すると考えられる。

Research Products

• [Journal Article] Autophagy is dispensable for the maintenance of hematopoietic stem cells in neonates (2021)
  • Author(s): Hashimoto Michihiro、Umemoto Terumasa、Nakamura-Ishizu Ayako、Matsumura Takayoshi、Yokomizo Tomomasa、Sezaki Maiko、Takizawa Hitoshi、Suda Toshio
  • Journal Title: Blood Advances Volume: 5 Issue: 6 Pages: 1594-1604
  • DOI: 10.1182/bloodadvances.2020002410
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity (2020)
  • Author(s): Mitsuhiro Endoh, Masaya Baba, Tamie Endoh, Akiyoshi Hirayama, Ayako Nakamura-Ishizu, Terumasa Umemoto, Michihiro Hashimoto, Kunio Nagashima, Tomoyoshi Soga, Martin Lang , Laura S Schmidt , W Marston Linehan, Toshio Suda
  • Journal Title: Cell Reports Volume: 30 Issue: 6 Pages: 1823-1834
  • DOI: 10.1016/j.celrep.2020.01.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Discrimination of dormant and active hematopoietic stem cells by G0 markers reveals dormancy regulation by cytoplasmic calcium. (2019)
  • Author(s): 5.Fukushima T, Tanaka Y, Hamey FK, Chang CH, Oki T, Asada S, Hayashi Y, Fujino T, Yonezawa T, Takeda R, Kawabata KC, Fukuyama T, Umemoto T, Takubo K, Takizawa H, Goyama S, Ishihama Y, Honda H, Gottgens B, Kitamura T.
  • Journal Title: Cell Rep Volume: 29 Issue: 12 Pages: 4144-4158
  • DOI: 10.1016/j.celrep.2019.11.061
  • NAID: 120006892032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Mitochondrial Mass Is Associated With Reconstitution Capacity and Quiescence of Hematopoietic Stem Cells (2019)
  • Author(s): Yuji Takihara, Ayako Nakamura-Ishizu, Darren Qiancheng Tan, Masahiro Fukuda, Takayoshi Matsumura, Mitsuhiro Endoh, Yuichiro Arima, Desmond Wai Loon Chin, Terumasa Umemoto, Michihiro Hashimoto, Hidenobu Mizuno, Toshio Suda
  • Journal Title: Blood Advances Volume: 3 Issue: 15 Pages: 2323-2327
  • DOI: 10.1182/bloodadvances.2019032169
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Reductive Glutamine metabolism regulates self-renew and differentiation in hematopoietic stem cells during bone marrow regeneration (2020)
  • Author(s): Terumasa Umemoto
  • Organizer: JSPS Core-to-Core Program Virtual Mini Symposium
  • Int'l Joint Research / Invited
• [Presentation] Low energy metabolism contributes to the maintenace of hematopoietic stem cells. (2019)
  • Author(s): Terumasa Umemoto, Michihiro Hashimoto, Toshio Suda
  • Organizer: 幹細胞シンポジウム
• [Presentation] エネルギー代謝を介した造血幹細胞の維持機構 (2019)
  • Author(s): Terumasa Umemoto, Michihiro Hashimoto, Toshio Suda
  • Organizer: 日本血液学会