Elucidation of the mechanism of asymmetric division of hematopoietic stem cells using the next-generation artificial niche

• Project/Area Number: 17H04208
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: Arai Fumio 九州大学, 医学研究院, 教授 (90365403)
• Co-Investigator(Kenkyū-buntansha): 国崎 祐哉 九州大学, 大学病院, 准教授 (80737099) ; 細川 健太郎 九州大学, 医学研究院, 講師 (90569584)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 造血幹細胞 / 非対称分裂 / ニッチ / ニッチ分子 / 間葉系幹細胞 / 人工ニッチ / 人工ニューラルネットワーク / 機械学習モデル / 自己複製分裂 / 対称・非対称分裂 / 再生医学 / 幹細胞ニッチ

Outline of Final Research Achievements

We tried to identify the niche factors and cell-intrinsic molecules regulating the self-renewal division of hematopoietic stem cells (HSCs). To find the niche factors, we profiled the gene expression in bone marrow stromal cells and found Igfbp5, Adipoq, and Ibsp in the mesenchymal stem cells. To analyze the division patterns, we combined the culture of HSC in the artificial niche and single-cell profiling of daughter cell pairs with machine learning. PEG microwells (PEG MW) were used as artificial niches. PEG MW increased self-renewal divisions and inhibited aging-associated gene expression in the daughter cells. We identified an essential set of 8 genes related to young HSC identity and 7 genes related to adult HSCs identity by conducting a model sensitivity analysis. These molecules are thought to function in a combinatorial manner.
In future issues, we need to clarify the function of the novel niche factors and cell-intrinsic molecules in the self-renewal of HSCs.

Academic Significance and Societal Importance of the Research Achievements

本研究により、複数のニッチ分子の候補が同定された。これらの分子が造血幹細胞の維持どのように関わるのかを解析した研究はなく、新規性の高い結果であると考えられた。PEG MWを用いた造血幹細胞の分裂解析において、自己複製分裂が増加していたことから、PEG MWは人工ニッチのベースとして優れた性能を持つと考えられた。今後、人工ニッチの改良、自己複製関連因子の機能解明を進めることで、効率の高いヒト造血幹細胞の体外増幅系の構築が可能となると考える。その成果は、骨髄移植における治療効果の増強、品質が保証された幹細胞の必要に応じた供給によるドナー不足の解消に貢献出来ると考える。

Research Products

• [Int'l Joint Research] サウサンプトン大学(英国)
• [Int'l Joint Research] ローザンヌ工科大学(スイス)
• [Int'l Joint Research] University of Southampton(英国)
• [Int'l Joint Research] Ecole Polytechnique Federale de Lausanne(スイス)
• [Journal Article] Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo. (2019)
  • Author(s): Kobayashi H, Morikawa T, Okinaga A, Hamano F, Hashidate-Yoshida T, Watanuki S, Hishikawa D, Shindou H, Arai F, Kabe Y, Suematsu M, Shimizu T, Takubo K.
  • Journal Title: Cell Reports Volume: 28 Issue: 1 Pages: 145-158
  • DOI: 10.1016/j.celrep.2019.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis (2019)
  • Author(s): Kidoya H, Muramatsu F, Shimamura T, Jia W, Satoh T, Hayashi Y, Naito H, Kunisaki Y, Arai F, Seki M, Suzuki Y, Osawa T, Akira S., Takakura N.
  • Journal Title: Nature Commun, Volume: 10 Issue: 1 Pages: 1072-1072
  • DOI: 10.1038/s41467-019-09028-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. (2019)
  • Author(s): Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, Ono N, Zolboot N, Aikawa Y, Oishi S, Nonami A, Arai F, Hagihara S, Yamaguchi J, Tama F, Kunisaki Y, Yagita K, Ikeda M, Kinoshita T, Kay SA, Itami K, Hirota T.
  • Journal Title: Science Advance Volume: 23 Issue: 1 Pages: 9060-9060
  • DOI: 10.1126/sciadv.aau9060
  • Peer Reviewed / Open Access / 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] The role of telomere binding molecules for normal and abnormal hematopoiesis. (2018)
  • Author(s): Hosokawa K, Arai F.
  • Journal Title: Int J Hematol. Volume: 印刷中 Issue: 6 Pages: 646-655
  • DOI: 10.1007/s12185-018-2432-4
  • Peer Reviewed / Open Access
• [Journal Article] Guest editorial: Regulatory signaling in normal and abnormal hematopoiesis (2018)
  • Author(s): Arai Fumio
  • Journal Title: International Journal of Hematology Volume: 107 Issue: 6 Pages: 624-626
  • DOI: 10.1007/s12185-018-2460-0
• [Journal Article] Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. (2018)
  • Author(s): Yamauchi T, et al.
  • Journal Title: Cancer Cell. Volume: 33 Issue: 3 Pages: 386-400
  • DOI: 10.1016/j.ccell.2018.01.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression (2017)
  • Author(s): Ali Mohamed A. E.、Fuse Kyoko、Tadokoro Yuko、Hoshii Takayuki、Ueno Masaya、Kobayashi Masahiko、Nomura Naho、Vu Ha Thi、Peng Hui、Hegazy Ahmed M.、Masuko Masayoshi、Sone Hirohito、Arai Fumio、Tajima Atsushi、Hirao Atsushi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11442-11442
  • DOI: 10.1038/s41598-017-11909-3
  • Peer Reviewed / Open Access
• [Journal Article] Stem Cell Differentiation as a Non-Markov Stochastic Process (2017)
  • Author(s): Stumpf Patrick S.、Smith Rosanna C.G.、Lenz Michael、Schuppert Andreas、Muller Franz-Josef、Babtie Ann、Chan Thalia E.、Stumpf Michael P.H.、Please Colin P.、Howison Sam D.、Arai Fumio、MacArthur Ben D.
  • Journal Title: Cell Systems Volume: 5 Issue: 3 Pages: 268-282.e7
  • DOI: 10.1016/j.cels.2017.08.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age (2017)
  • Author(s): Hosokawa Kentaro、MacArthur Ben D.、Ikushima Yoshiko Matsumoto、Toyama Hirofumi、Masuhiro Yoshikazu、Hanazawa Shigemasa、Suda Toshio、Arai Fumio
  • Journal Title: Nature Communications Volume: 8(804) Issue: 1 Pages: 804-818
  • DOI: 10.1038/s41467-017-00935-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The novel mesenchymal stromal niche cell in the bone marrow endosteum (2018)
  • Author(s): Fumio Arai
  • Organizer: 9th International Conference and Exhibition on Tissue Science and Regenerative Medicine
  • Int'l Joint Research / Invited
• [Presentation] Regulation of asymmetric division of hematopoietic stem cell by Angiopoietin-1 (2018)
  • Author(s): Arai Fumio、MacArthur Ben D.
  • Organizer: Japan Society for the Promotion of Science and National University of Singapore joint 2nd symposium
  • Int'l Joint Research / Invited
• [Presentation] Pot1 maintains haematopoietic stem cell activity by protecting against DNA damage and metabolic alterations (2017)
  • Author(s): Arai Fumio
  • Organizer: 8th International Conference on Tissue Science and Regenerative Medicine
  • Int'l Joint Research / Invited
• [Presentation] Identification of novel mesenchymal stromal cells that have the potential to support hematopoietic stem cell activity (2017)
  • Author(s): Arai Fumio
  • Organizer: 7th International Conference on Tissue Engineering and Regenerative Medicine
  • Int'l Joint Research / Invited
• [Remarks] 九州大学大学院医学研究院幹細胞再生修復医学分野ホームページ
  • URL: https://www.lab.med.kyushu-u.ac.jp/scr/
• [Remarks] 造血幹細胞の機能維持と老化を制御する分子を同定
  • URL: http://www.med.kyushu-u.ac.jp/app/modules/information/database_detail.php?i=975&s=0&k=