Investigation of developmental regulators for human hematopoietic stem cells and downstream road-blocker(s) of Lhx2
Project/Area Number |
16H04728
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Medical genome science
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Research Institution | Tokyo Metropolitan Institute of Medical Science |
Principal Investigator |
HARA Takahiko 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 分野長 (80280949)
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Co-Investigator(Kenkyū-buntansha) |
北島 健二 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 主席研究員 (10346132)
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Research Collaborator |
Takahashi yuna
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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Keywords | 造血幹細胞 / iPS細胞 / 転写因子 / 造血発生 |
Outline of Final Research Achievements |
Transcription factor Lhx2 is capable to expanding mouse embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived hematopoietic stem cells (HSCs). In contrast, in the in vitro differentiation culture of human iPSCs, Lhx2 strongly suppresses hematopoietic cell differentiation. We searched for a responsible domain of this Lhx2’s differentiation block activity. We found that a LIM2 domain point mutant of Lhx2 lacks the differentiation block activity in human iPSCs as well as a growth suppressive effect of Lhx2 in a myeloid leukemia-derived cell line K562. Lhx2-LIM2 mutant also lost ex vivo HSC expansion capacity in mouse ESCs. By way of transcriptional profiling of Lhx2 downstream genes in K562 cells, we discovered that nine transcription factors including GFI1B and KLF1 are robustly downregulated by overexpression of Lhx2, but not Lhx2-LIM2 mutant, in K562 cells. These changes may be a reason why Lhx2 blocks the hematopoietic cell differentiation in human iPSC.
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Academic Significance and Societal Importance of the Research Achievements |
白血病患者の根本治療法として、患者のHLAにマッチした造血幹細胞の移植治療が実施されている。そのソースとして骨髄バンクや臍帯血バンクが整備されているが、少子化と高齢化が進んでいる我が国ではストックは年々減少しており、決して安心できる状況とは言えない。もし、ヒトiPS細胞から造血幹細胞を作り出せるようになれば、造血幹細胞移植のソースを安定的に供給できるようになると期待される。したがって、マウスでは成功しているiPS細胞から造血幹細胞を体外増幅する方法が、何故ヒトiPS細胞ではうまくいかないのかを早急に解明する必要がある。
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Report
(4 results)
Research Products
(36 results)
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[Journal Article] Transfer of a mouse artificial chromosome into spermatogonial stem cells genetates transchromosomic mice,2017
Author(s)
Shinohara T, Kazuki K, Ogonuki N, Morimoto H, Matoba S, Hiramatsu K, Honma K, Suzuki T, Hara T, Ogura A, Oshimura M, Kanatsu-Shinohara M, Kazuki Y.
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Journal Title
Stem Cell Reports.
Volume: 9(4)
Issue: 4
Pages: 1180-1191
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Growth Suppressing Activity of Lhx2 in Human T Cell Acute Lymphoblastic Leukemia (T-ALL)-derived Cells and Large-scale Screening of Lead Compounds Targeting T-ALL.2016
Author(s)
K. Miyashita, N. Kagaya, M. Izumikawa, K. Kitajima, K. Watakabe-Inamoto, Y. Najima, N. Doki, T. Kobayashi, K. Kakihana, S. Goyama, T. Kitamura, K. Ohashi, K. Shin-ya, and T. Hara.
Organizer
58th ASH (American Society of Hematology) Annual Meeting and Exposition
Place of Presentation
San Diego, USA
Year and Date
2016-12-03
Related Report
Int'l Joint Research
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[Presentation] 急性Tリンパ芽球性白血病を標的としたリード化合物の探索.2016
Author(s)
宮下和也, 加賀谷紀貴, 泉川美穂, 稲本恭子, 名島悠峰, 土岐典子, 小林 武, 垣花和彦,合山 進, 北村俊雄, 大橋一輝, 新家一男, 原 孝彦.
Organizer
第39回日本分子生物学会年会
Place of Presentation
パシフィコ横浜(神奈川県横浜市)
Year and Date
2016-11-30
Related Report
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