Construction of artificial bone marrow microenvironment that maintains undifferentiated state of hematopoietic stem cells

• Project/Area Number: 25713037
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: Yamazaki Satoshi 東京大学, 医科学研究所, 特任准教授 (50625580)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥22,880,000 (Direct Cost: ¥17,600,000、Indirect Cost: ¥5,280,000); Fiscal Year 2016: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2013: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 造血幹細胞 / 幹細胞ニッチ / 骨髄微小環境 / 人工ニッチ / 骨髄ニッチ / 人口ニッチ / 幹細胞増幅 / 造血幹細胞移植

Outline of Final Research Achievements

Hematopoietic stem cells are maintained undifferentiated in the bone marrow microenvironment. However, we have not yet fully enabled the control of hematopoietic stem cells. We found heterogeneity of amino acid concentration in bone marrow, and analyzed function of each amino acid and hematopoietic stem cell. As a result, the hematopoietic stem cells quickly disappeared under the culturing condition of valine deficiency, and the reduction of hematopoietic stem cells in vivo was confirmed by giving the valine-deficient diet to the mouse for a long time. In addition, interesting results were obtained that transplantation of hematopoietic stem cells was established without irradiation by giving valine-deficient diet to recipient mice, and the article was accepted in Science Journal Science of the United States of America (Taya et al., 2016).

Research Products

• [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] 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] 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] 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] Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenyous 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: 11 Pages: 223-227
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy. (2015)
  • Author(s): Ando M, Nishimura T, Yamazaki S, Yamaguchi T, Kawana-Tachikawa A, Hayama T, Nakauchi Y, Ando J, Ota Y, Takahashi S, Nishimura K, Ohtaka M, Nakanishi M, Miles JJ, Burrows SR, Brenner MK, Nakauchi H.
  • Journal Title: Stem Cell Reports. Volume: 5(4) Issue: 4 Pages: 597-608
  • DOI: 10.1016/j.stemcr.2015.07.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell Adhesion Minimization by a Novel Mesh Culture Method Mechanically Directs Trophoblast Differentiation and Self-Assembly Organization of Human Pluripotent Stem Cells (2015)
  • Author(s): Okeyo O. Kennedy, Osamu Kurosawa, Satoshi Yamazaki, Hidehiro Oana, Hidetoshi Kotera, Hiromitsu Nakauchi, Masao Washizu
  • Journal Title: Tissue Engineering Part C Volume: なし Issue: 10 Pages: 1105-15
  • DOI: 10.1089/ten.tec.2015.0038
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse mode (2015)
  • Author(s): Nakauchi Y, Yamazaki S, Napier SC, Usui J, Ota Y, Takahashi S, Watanabe N, Nakauchi H
  • Journal Title: Experimental hematology Volume: 43 Issue: 2 Pages: 79-88
  • DOI: 10.1016/j.exphem.2014.10.008
  • Peer Reviewed / Open Access
• [Journal Article] Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients (2014)
  • Author(s): Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Yuasa S, Yamazaki S, Nishimura T, Sadahira K, Fukuda K, Okano H, Nakauchi H, Morita Y, Matsumura I, Kudo K, Ito E, Ebihara Y, Tsuji K, Harada Y, Harada H, Okamoto S, Nakajima H
  • Journal Title: Leukemia Volume: 28 Issue: 12 Pages: 2344-54
  • DOI: 10.1038/leu.2014.136
  • Peer Reviewed / Open Access
• [Journal Article] Bone marrow Schwann cells induce hematopoietic stem cell hibernation (2014)
  • Author(s): Yamazaki S, Nakauchi H
  • Journal Title: International journal of hematology Volume: 99 Issue: 6 Pages: 695-8
  • DOI: 10.1007/s12185-014-1588-9
  • Peer Reviewed / Open Access
• [Journal Article] A melanocyte--melanoma precursor niche in sweat glands of volar skin. (2014)
  • Author(s): Okamoto N, Aoto T, Uhara H, Yamazaki S, Akutsu H, Umezawa A, Nakauchi H, Miyachi Y, Saida T, Nishimura EK.
  • Journal Title: Pigment Cell Melanoma Res Volume: 27 Issue: 6 Pages: 1039-1350
  • DOI: 10.1111/pcmr.12297
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gene Targeting Study Reveals Unexpected Expression of Brain expressed X-linked 2 in Endocrine and Tissue Stem/progenitor Cells in Mice (2014)
  • Author(s): Keiichi Ito, Satoshi Yamazaki, Ryo Yamamoto, Yoko Tajima, Ayaka Yanagida, Toshihiro Kobayashi, Megumi Kato-Itoh, Shigeru Kakuta, Yoichiro Iwakura, Hiromitsu Nakauchi, Akihide Kamiya,
  • Journal Title: J Biol Chem Volume: 289(43) Issue: 43 Pages: 29892-911
  • DOI: 10.1074/jbc.m114.580084
  • Peer Reviewed / Open Access
• [Journal Article] Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies (2014)
  • Author(s): Kazuki Y, Yakura Y, Abe S, Osaki M, Kajitani N, Kazuki K, Takehara S, Honma K, Suemori H, Yamazaki S, Sakuma T, Toki T, Shimizu R, Nakauchi H, Yamamoto T, Oshimura M
  • Journal Title: Scientific reports Volume: 4 Issue: 1 Pages: 6136-6136
  • DOI: 10.1038/srep06136
  • Peer Reviewed / Open Access
• [Journal Article] Generation of Functional Oocytes by Xeno-Ectopic Transplantation of Primordial Germ Cells (2014)
  • Author(s): Hayama T, Yamaguchi T, Kato-Itoh M, Hamanaka S, Kawarai M, Sanbo M, Tamura C, Lee YS, Yanagida A, Murayama H, Mizuno N, Umino A, Sato H, Yamazaki S, Masaki H, Kobayashi T, Hirabayashi M, Nakauchi H
  • Journal Title: Biol Reprod Volume: 91(4) 89 Issue: 4 Pages: 1-9
  • DOI: 10.1095/biolreprod.114.121640
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Generation of recombination activating gene-1-deficient neonatal piglets: a model of T and B cell deficient severe combined immune deficiency. (2014)
  • Author(s): Ito T, Sendai Y, Yamazaki S, Seki-Soma M, Hirose K, Watanabe M, Fukawa K, Nakauchi H.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e113833-e113833
  • DOI: 10.1371/journal.pone.0113833
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clock gene Bmal1 is dispensable for intrinsic properties of murine hematopoietic stem cells. (2014)
  • Author(s): Ieyasu A, Tajima Y, Shimba S, Nakauchi H, Yamazaki S.
  • Journal Title: J Negat Results Biomed. Volume: 8
  • Peer Reviewed
• [Journal Article] The TIF1β-HP1 System Maintains Transcriptional Integrity of Hematopoietic Stem Cells. (2014)
  • Author(s): Miyagi S, Koide S, Saraya A, Wendt GR, Oshima M, Konuma T, Yamazaki S, Mochizuki-Kashio M, Nakajima-Takagi Y, Wang C, Chiba T, Kitabayashi I, Nakauchi H, Iwama A
  • Journal Title: Stem Cell Reports Volume: 23 Pages: 145-152
  • Peer Reviewed
• [Journal Article] Stage-specific roles for Cxcr4 signaling in murine hematopoietic stem/progenitor cells in the process of bone marrow repopulation. (2014)
  • Author(s): Lai CY, Yamazaki S, Okabe M, Suzuki S, Maeyama Y, Iimura Y, Onodera M, Kakuta S, Iwakura Y, Nojima M, Otsu M, Nakauchi H.
  • Journal Title: Stem Cells Volume: 8
  • Peer Reviewed
• [Journal Article] Immortalization of Erythroblasts by c-MYC and BCL-XL Enables Large-Scale Erythrocyte Production from Human Pluripotent Stem Cells. (2013)
  • Author(s): Hirose S, Takayama N, Nakamura S, Nagasawa K, Ochi K, Hirata S, Yamazaki S, Yamaguchi T, Otsu M, Sano S, Takahashi N, Sawaguchi A, Ito M, Kato T, Nakauchi H, Eto K.
  • Journal Title: Stem Cell Reports Volume: 5 Pages: 499-508
  • NAID: 120005350227
  • Peer Reviewed
• [Journal Article] Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. (2013)
  • Author(s): Suzuki N, Yamazaki S, Yamaguchi T, Okabe M, Masaki H, Takaki S, Otsu M, Nakauchi H.
  • Journal Title: Mol Ther Volume: 21 Pages: 1424-1231
  • Peer Reviewed
• [Presentation] 造血幹細胞を維持する骨髄ニッチ (2014)
  • Author(s): 山崎聡
  • Organizer: 日本再生医療学会
  • Place of Presentation: 京都国際会議場
  • Invited
• [Remarks] 東京大学医科学研究所
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/lab/stemcell/
• [Remarks] 幹細胞治療研究センター
  • URL: http://stemcell-u-tokyo.org/sct/