Energy metabolism-dependent selection of self-renewal and differnetiation in HSCs

• Project/Area Number: 19H03688
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• 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): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 造血幹細胞 / エネルギー代謝

Outline of Research at the Start

造血幹細胞は造血システムにおいて最も中心的な役割を果たす体性幹細胞として知られているが、その自己複製分裂の制御機構においては未だ不明な点が多い。これまでに申請者らは、分裂誘導時に上昇する造血幹細胞の細胞内Ca2+/ミトコンドリア膜電位を抑制することが、分裂後の幹細胞の運命を「分化」から「幹細胞性維持」にシフトさせることを見出している。本研究では、分裂誘導刺激時のエネルギー代謝の状態が自己複製分裂・分化分裂のスイッチと働くことを明らかにし、造血幹細胞の自己複製分裂のメカニズムに迫ることを目的とする。

Outline of Final Research Achievements

In this study, through the study regarding HSCs during bone marrow regeneration, we found that the regulation of chromatin status in HSCs is essential to determine cell fate after HSC divisions. Moreover, we show that Acly, an essential enzyme in reductive glutamine metabolic pathway, and mitochondrial metabolism regulate expression of genes having increased accessibility within cis-elementary regions through histone acetylation.

Academic Significance and Societal Importance of the Research Achievements

本研究において、造血幹細胞の運命決定におけるクロマチン動態制御、及び造血幹細胞の機能制御における代謝制御の役割が明らかになり、「クロマチン動態と代謝制御」が協調して幹細胞機能を制御しているという、新たな理解を示した。これらの発見により、造血幹細胞の機能制御の理解が深まることで、再生治療・遺伝子治療を視野に入れた試験管内における幹細胞操作方法の開発や、抗癌剤投与の副作用として知られている骨髄抑制の新規治療法の開発等に寄与することが期待される。

Research Products

• [Journal Article] ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration (2022)
  • Author(s): Umemoto Terumasa、Johansson Alban、Ahmad Shah Adil Ishtiyaq、Hashimoto Michihiro、Kubota Sho、Kikuchi Kenta、Odaka Haruki、Era Takumi、Kurotaki Daisuke、Sashida Goro、Suda Toshio
  • Journal Title: The EMBO Journal Volume: 41 Issue: 8 Pages: 1-20
  • DOI: 10.15252/embj.2021109463
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer (2022)
  • Author(s): Fu Lingfeng、Yonemura Atsuko、Yasuda-Yoshihara Noriko、Umemoto Terumasa、Zhang Jun、Yasuda Tadahito、Uchihara Tomoyuki、Akiyama Takahiko、Kitamura Fumimasa、Yamashita Kohei、Okamoto Yuya、Bu Luke、Wei Feng、Hu Xichen、Liu Yang、Ajani Jaffer A.、Tan Patrick、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Gastric Cancer Volume: 25 Issue: 3 Pages: 542-557
  • DOI: 10.1007/s10120-022-01283-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors (2022)
  • Author(s): Tanaka Yosuke....Goyama Susumu、Komatsu Norio、Takaku Tomoiku、Kitamura Toshio
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 271-271
  • DOI: 10.1038/s41467-021-27928-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 還元的グルタミン代謝を介した造血幹細胞制御 (2021)
  • Author(s): Terumasa Umemoto, Alban Johansson, Shah Adil Ishtiyaq Ahmad, Michihiro Hashimoto, Sho Kubota, Haruki Odaka, Takumi Era, Goro Sashida, Toshio Suda
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] The metabolic fitness corresponding to chromatin accessibility patterns is essential for hematopoietic stem cell regulations (2021)
  • Author(s): Terumasa Umemoto, Alban Johansson, Shah Adil Ishtiyaq Ahmad, Michihiro Hashimoto, Sho Kubota, Haruki Odaka, Takumi Era, Goro Sashida, Toshio Suda
  • Organizer: 第18回幹細胞シンポジウム
• [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