Hematopoietic stem cell control by amino acids and development of novel therapeutic methods

• Project/Area Number: 16H02661
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: Hiromitsu Nakauchi 東京大学, 医科学研究所, 特任教授 (40175485)
• Co-Investigator(Kenkyū-buntansha): 山崎 聡 東京大学, 医科学研究所, 特任准教授 (50625580)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000); Fiscal Year 2018: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000); Fiscal Year 2017: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥20,540,000 (Direct Cost: ¥15,800,000、Indirect Cost: ¥4,740,000)
• Keywords: 造血幹細胞 / 骨髄ニッチ / アミノ酸 / バリン / BCAA / 骨髄移植 / アミノ酸バランス / 骨髄微小環境 / 骨髄環境 / 造血幹細胞移植学 / 培地

Outline of Final Research Achievements

A specialized bone marrow microenvironment (niche) regulates hematopoietic stem cell (HSC) self-renewal and commitment. For successful donor-HSC engraftment, the niche must be emptied via myeloablative irradiation or chemotherapy. However, myeloablation can cause severe complications and even mortality. We found that the essential amino acid valine is indispensable for the proliferation and maintenance of HSCs. Both mouse and human HSCs failed to proliferate when cultured in valine-depleted conditions. In mice fed a valine-restricted diet, HSC frequency fell dramatically within 1 week. Furthermore, dietary valine restriction emptied the mouse bone marrow niche and afforded donor-HSC engraftment without chemoirradiative myeloablation. These project findings a critical role for valine in HSC maintenance and suggest that dietary valine restriction may reduce iatrogenic complications in HSC transplantation.

Academic Significance and Societal Importance of the Research Achievements

研究期間内に我々は，造血にアミノ酸のバランスが非常に重要であることが示された。これらの発見は今後の骨髄ニッチの機能および造血についてのさらなる研究が期待される。また，造血幹細胞と骨髄ニッチとの相互作用と同様の概念が白血病幹細胞においても提唱されていることから、バリンの欠乏した環境が造血幹細胞と同様に白血病細胞など悪性腫瘍においても効果が期待でき、アミノ酸の制御は移植の前処置やがんの分野においても新しい治療法となる可能性が示唆できることから、社会的な意義や波紋は大きかった。

Research Products

• [Journal Article] Changing concepts in hematopoietic stem cells. (2018)
  • Author(s): Yamamoto R, Wilkinson AC, Nakauchi H.
  • Journal Title: Science Volume: 362 Issue: 6417 Pages: 895-896
  • DOI: 10.1126/science.aat7873
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia. (2018)
  • Author(s): van Galen P, Mbong N, Kreso A, Schoof EM, Wagenblast E, Ng SWK, Krivdova G, Jin L, Nakauchi H, Dick JE.
  • Journal Title: Cell Rep Volume: 25 Issue: 5 Pages: 1109-1117
  • DOI: 10.1016/j.celrep.2018.10.021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate. (2018)
  • Author(s): 1.Taoka K, Arai S, Kataoka K, Hosoi M, Miyauchi M, Yamazaki S, Honda A, Aixinjueluo W, Kobayashi T, Kumano K, Yoshimi A, Otsu M, Niwa A, Nakahata T, Nakauchi H, Kurokawa M.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15855-15867
  • DOI: 10.1038/s41598-018-34193-1
  • NAID: 120006534582
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of Vascular Endothelial Cells and Hematopoietic Cells by Blastocyst Complementation. (2018)
  • Author(s): Hamanaka S, Umino A, Sato H, Hayama T, Yanagida A, Mizuno N, Kobayashi T, Kasai M, Suchy FP, Yamazaki S, Masaki H, Yamaguchi T, Nakauchi H.
  • Journal Title: Stem Cell Reports. Volume: 11(4) Issue: 4 Pages: 988-997
  • DOI: 10.1016/j.stemcr.2018.08.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Designing Motif-Engineered Receptors To Elucidate Signaling Molecules Important for Proliferation of Hematopoietic Stem Cells. (2018)
  • Author(s): Ishizuka S, Lai CY, Otsu M, Nakauchi H, Nagamune T, Kawahara M.
  • Journal Title: ACS Synth Biol. Volume: 7 Issue: 7 Pages: 1709-1714
  • DOI: 10.1021/acssynbio.8b00163
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress (2018)
  • Author(s): Tadokoro Yuko、Hoshii Takayuki、Yamazaki Satoshi、Eto Koji、Ema Hideo、Kobayashi Masahiko、Ueno Masaya、Ohta Kumiko、Arai Yuriko、Hara Eiji、Harada Kenichi、Oshima Masanobu、Oshima Hiroko、Arai Fumio、Yoshimura Akihiko、Nakauchi Hiromitsu、Hirao Atsushi
  • Journal Title: Cell Stem Cell Volume: 22 Issue: 5 Pages: 713-725
  • DOI: 10.1016/j.stem.2018.04.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity. (2018)
  • Author(s): Wilkinson AC, Morita M, Nakauchi H, Yamazaki S.
  • Journal Title: Exp Hematol. Volume: 63 Pages: 12-16
  • DOI: 10.1016/j.exphem.2018.04.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment. (2018)
  • Author(s): Yamamoto, R., Wilkinson, A.C., Ooehara, J., Lan, X., Lai, C.Y., Nakauchi, Y., Pritchard, J.K., and Nakauchi, H.
  • Journal Title: Cell Stem Cell Volume: 22 Issue: 4 Pages: 600-607
  • DOI: 10.1016/j.stem.2018.03.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dissection of Signaling Events Downstream of the c-Mpl Receptor in Murine Hematopoietic Stem Cells Via Motif-Engineered Chimeric Receptors (2018)
  • Author(s): Saka Koichiro、Lai Chen-Yi、Nojima Masanori、Kawahara Masahiro、Otsu Makoto、Nakauchi Hiromitsu、Nagamune Teruyuki
  • Journal Title: Stem Cell Rev. Rep. Volume: 14 Issue: 1 Pages: 101-109
  • DOI: 10.1007/s12015-017-9768-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PhysiologicalSrsf2P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice (2017)
  • Author(s): Kon Ayana、Yamazaki Satoshi、Nannya Yasuhito、Kataoka Keisuke、Ota Yasunori、Nakagawa Masahiro Marshall、Yoshida Kenichi、Shiozawa Yusuke、Morita Maiko、Yoshizato Tetsuichi、Sanada Masashi、Nakayama Manabu、Koseki Haruhiko、Nakauchi Hiromitsu、Ogawa Seishi
  • Journal Title: Blood Volume: 131 Issue: 6 Pages: 621-635
  • DOI: 10.1182/blood-2017-01-762393
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Continuous cell supply from Krt7-expressing hematopoietic stem cells during native hematopoiesis revealed by targeted in vivo gene transfer method. (2017)
  • Author(s): Tajima Y, Ito K, Umino A, Wilkinson AC, Nakauchi H, Yamazaki S
  • Journal Title: Sci Rep Volume: 18 Issue: 1 Pages: 40684-40684
  • DOI: 10.1038/srep40684
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 1.An All-Recombinant Protein-Based Culture System Specifically Identifies Hematopoietic Stem Cell Maintenance Factors. (2017)
  • Author(s): Ieyasu A, Ishida R, Kimura T, Morita M, Wilkinson AC, Sudo K, Nishimura T, Ohehara J, Tajima Y, Lai CY, Otsu M, Nakamura Y, Ema H, Nakauchi H, Yamazaki S
  • Journal Title: Stem Cell Reports Volume: 14 Issue: 3 Pages: 500-508
  • DOI: 10.1016/j.stemcr.2017.01.015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome (2017)
  • Author(s): 1.Shimazu H, Munakata S, Tashiro Y, Salama Y, Eiamboonser S, Ohta Y, Onoda H, Tsuda Y, Okada Y, Nakauchi H, Heissig B and Hattori K
  • Journal Title: Blood Volume: 印刷中 Issue: 1 Pages: 59-72
  • DOI: 10.1182/blood-2016-09-738096
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] In?Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos , and Gata2 Overexpression within Teratoma (2017)
  • Author(s): Tsukada Masao、Ota Yasunori、Wilkinson Adam C.、Becker Hans J.、Osato Motomi、Nakauchi Hiromitsu、Yamazaki Satoshi
  • Journal Title: Stem Cell Reports Volume: 9 Issue: 4 Pages: 1024-1033
  • DOI: 10.1016/j.stemcr.2017.08.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Mouse Model of iNKT Cell-deficiency Generated by CRISPR/Cas9 Reveals a Pathogenic Role of iNKT Cells in Metabolic Disease. (2017)
  • Author(s): Ren Y, Sekine-Kondo E, Shibata R, Kato-Itoh M, Umino A, Yanagida A, Satoh M, Inoue K, Yamaguchi T, Mochida K, Nakae S, Van Kaer L, Iwabuchi K, Nakauchi H, Watarai H.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 12765-12765
  • DOI: 10.1038/s41598-017-12475-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity (2017)
  • Author(s): Wilkinson Adam C.、Nakauchi Hiromitsu、G?ttgens Berthold
  • Journal Title: Cell Syst Volume: 5 Issue: 4 Pages: 319-331
  • DOI: 10.1016/j.cels.2017.07.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel TPO receptor agonist TA-316 contributes to platelet biogenesis from human iPS cells. (2017)
  • Author(s): Ayako Aihara, Tomo Koike, Natsuki Abe, Sou Nakamura, Akira Sawaguchi, Takanori Nakamura, Naoshi Sugimoto, Hiromitsu Nakauchi, Taito Nishino and Koji Eto
  • Journal Title: Blood Advances Volume: 1 Issue: 7 Pages: 468-476
  • DOI: 10.1182/bloodadvances.2016000844
  • NAID: 120006488581
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells. (2017)
  • Author(s): Ishida T, Suzuki S, Lai CY, Yamazaki S, Kakuta S, Iwakura Y, Nojima M, Takeuchi Y, Higashihara M, Nakauchi H, Otsu M.
  • Journal Title: Stem Cells. Volume: 35 Issue: 4 Pages: 989-1002
  • DOI: 10.1002/stem.2524
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche (2016)
  • Author(s): Chen JY, Miyanishi M, Wang SK, Yamazaki S, Sinha R, Kao KS, Seita J, Sahoo D, Nakauchi H, Weissman IL
  • Journal Title: Nature Volume: 530(7589) Issue: 7589 Pages: 223-7
  • DOI: 10.1038/nature16943
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spatiotemporal Reconstruction of the Human Blastocyst by Single-Cell Gene-Expression Analysis Informs Induction of Naive Pluripotency (2016)
  • Author(s): Durruthy-Durruthy, J., Wossidlo, M., Pai, S., Takahashi, Y., Kang, G., Omberg, L., Chen, B., Nakauchi, H., Reijo Pera, R. and Sebastiano, V
  • Journal Title: Dev Cell Volume: 38 Issue: 1 Pages: 100-15
  • DOI: 10.1016/j.devcel.2016.06.014
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple allogeneic progenitors in combination function as a unit to support early transient hematopoiesis in transplantation (2016)
  • Author(s): Ishida, T., Takahashi, S., Lai, C. Y., Nojima, M., Yamamoto, R., Takeuchi, E., Takeuchi, Y., Higashihara, M., Nakauchi, H. and Otsu, M
  • Journal Title: J Exp Med Volume: 213 Pages: 1865-80
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of non-hematopoietic genes. (2016)
  • Author(s): Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, Chiba T, Matsui H, Arai F, Suzuki Y, Kimura H, Nakauchi H, Suda T, Shinkai Y,Iwama A.
  • Journal Title: Blood Volume: 128(5) Issue: 5 Pages: 638-649
  • DOI: 10.1182/blood-2016-01-694810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation (2016)
  • Author(s): Taya, Y., Ota, Y., Wilkinson, A. C., Kanazawa, A., Watarai, H., Kasai, M., Nakauchi, H. and Yamazaki, S
  • Journal Title: Science Volume: 354 Issue: 6316 Pages: 1152-1155
  • DOI: 10.1126/science.aag3145
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Non-myeloablative preconditioning with ACK2 (anti-c-kit antibody) is efficient in bone marrow transplantation for murine models of mucopolysaccharidosis type II (2016)
  • Author(s): Yokoi, T., Yokoi, K., Akiyama, K., Higuchi, T., Shimada, Y., Kobayashi, H., Sato, T., Ohteki, T., Otsu, M., Nakauchi, H., Ida, H. and Ohashi, T
  • Journal Title: Mol Genet Meta Volume: 119 Issue: 3 Pages: 232-238
  • DOI: 10.1016/j.ymgme.2016.08.003
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Ex vivo expansion of hematopoietic stem cells: Dream or reality? (2019)
  • Author(s): 中内 啓光
  • Organizer: Prof. Ken-ichi Arai Memorial Symposium
  • Invited
• [Presentation] iPS細胞から臓器をつくる： 国境を跨いだ挑戦 (2019)
  • Author(s): 中内 啓光
  • Organizer: ＮＰＯ健康医療開発機構 細胞医療の時代2018シリーズ 「第7回 細胞移植から臓器移植へ」
  • Invited
• [Presentation] Stable ex vivo HSC expansion: dream or reality? (2018)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Cambridge Stem Cell Symposium: UK CSCIS Opening Symposium
  • Int'l Joint Research / Invited
• [Presentation] Clonal analysis of young and aged hematopoietic stem cells (2018)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Mini Symposium at Lund University
  • Int'l Joint Research / Invited
• [Presentation] 幹細胞ニッチ：細胞から臓器へ～ (2017)
  • Author(s): 中内 啓光
  • Organizer: 東京免疫フォーラム
  • Place of Presentation: 東京大学医科学研究所、東京
  • Year and Date: 2017-03-23
  • Int'l Joint Research / Invited
• [Presentation] 幹細胞ニッチ：細胞から臓器へ (2017)
  • Author(s): 中内 啓光
  • Organizer: 東京免疫フォーラム
  • Invited
• [Presentation] 幹細胞とアミノ酸バランス (Stem Cells and Amino Acid Balance) (2017)
  • Author(s): 中内 啓光
  • Organizer: 日本癌学会ランチョンセミナー
  • Invited
• [Presentation] 幹細胞ニッチの概念を利用した新しい医療 (2017)
  • Author(s): 中内 啓光
  • Organizer: 第９回血液疾患免疫療法学会学術集会共催ランチョンセミナー
  • Invited
• [Presentation] Clonal Analysis of Young and Aged Hematopoietic Stem Cells (2017)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Regenerative Medicine Seminar Series (ReMS)
  • Int'l Joint Research / Invited
• [Presentation] Stem Cell Niche: From Cells to Organs (2017)
  • Author(s): 中内 啓光
  • Organizer: Cell Press Lablinks
  • Invited
• [Presentation] From Stem Cells to Organs: Exploiting the organ niche for interspecies organogenesis (2016)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Erasmus MC workshop
  • Place of Presentation: Rotterdam, Netherland
  • Year and Date: 2016-11-23
  • Int'l Joint Research / Invited
• [Presentation] Stem Cell niche--from cells to organs (2016)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: 7th Annual Stem Cell Biology and Regenerative Medicine Retreat
  • Place of Presentation: Monterey, California,USA
  • Year and Date: 2016-09-27
  • Int'l Joint Research / Invited
• [Presentation] From Stem Cells to Organs: Exploiting the organ niche for interspecific organogenesis (2016)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Advances in Organogenesis and Tissue Engineering Symposia at John Hopkins University
  • Place of Presentation: Baltimore, Maryland,USA
  • Year and Date: 2016-05-25
  • Int'l Joint Research / Invited
• [Presentation] Stem Cell Niche-From Cells to Organs (2016)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: University of Southern California
  • Place of Presentation: Los Angeles, California,USA
  • Year and Date: 2016-05-17
  • Int'l Joint Research / Invited
• [Presentation] Stem cell niche" from cells and organs (2016)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Stower’s Li Lab
  • Place of Presentation: Kansas City, Missouri,USA
  • Year and Date: 2016-05-04
  • Int'l Joint Research / Invited
• [Patent(Industrial Property Rights)] 成人Ｔ細胞白血病リンパ腫を処置することに用いるための組成物およびその製造方法 (2019)
  • Inventor(s): 中内啓光、石垣知寛、山崎聡、田矢祐規
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-531993
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 成人Ｔ細胞白血病リンパ腫を処置することに用いるための組成物およびその製造方法 (2019)
  • Inventor(s): 中内啓光、石垣知寛、山崎聡、田矢祐規
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] 成人Ｔ細胞白血病リンパ腫を処置することに用いるための組成物およびその製造方法 (2019)
  • Inventor(s): 中内啓光、石垣知寛、山崎聡、田矢祐規
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] 造血幹細胞を減少させる組成物およびその製造方法 (2018)
  • Inventor(s): 中内啓光、山崎聡、田矢裕規
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Acquisition Date: 2018
• [Patent(Industrial Property Rights)] 成人Ｔ細胞白血病リンパ腫を処置することに用いるための組成物およびその製造方法 (2017)
  • Inventor(s): 中内啓光、山崎聡、石垣知寛、田矢祐規
  • Industrial Property Rights Holder: 中内啓光、山崎聡、石垣知寛、田矢祐規
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] 成人T細胞白血病リンパ腫を処置することに用いるための組成物およびその製造方法 (2016)
  • Inventor(s): 中内啓光、石垣知寛、山崎聡、田矢祐規
  • Industrial Property Rights Holder: 国立大学法人 東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-08-05