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Investigation of developmental regulators for human hematopoietic stem cells and downstream road-blocker(s) of Lhx2

Research Project

Project/Area Number 16H04728
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical genome science
Research InstitutionTokyo 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)

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)
Research Collaborator Takahashi yuna  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
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)
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.

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。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (36 results)

All 2019 2018 2017 2016 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (20 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Remarks (3 results) Patent(Industrial Property Rights) (3 results)

  • [Journal Article] Latrophilin2 is involved in neural crest cell migration and placode patterning in Xenopus laevis.2019

    • Author(s)
      Yokote N., Suzuki-Kosaka Y. M., Michiue T., Hara T., Tanegashima K.
    • Journal Title

      International Journal of Developmental Biology

      Volume: 63 Issue: 1-2 Pages: 29-35

    • DOI

      10.1387/ijdb.180184kt

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibitory action of an ERK1/2 inhibitor on primitive endoderm cell differentiation from mouse embryonic stem cells.2019

    • Author(s)
      H. Tabata, T. Hara, and K. Kitajima.
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 512 Issue: 2 Pages: 399-404

    • DOI

      10.1016/j.bbrc.2019.03.081

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene.2018

    • Author(s)
      K. Tanaka, N. Ikeda, K. Miyashita, H. Nuriya, and T. Hara.
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 8 Pages: 2479-2489

    • DOI

      10.1111/cas.13661

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Domain-specific biological functions of the transcription factor Gata2 on hematopoietic differentiation of mouse embryonic stem cells2018

    • Author(s)
      Kitajima Kenji、Kanokoda Mai、Nakajima Marino、Hara Takahiko
    • Journal Title

      Genes to Cells

      Volume: 23 Issue: 9 Pages: 753-766

    • DOI

      10.1111/gtc.12628

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overexpression of Lhx2 suppresses proliferation of human T cell acute lymphoblastic leukemia-derived cells, partly by reducing LMO2 protein levels2018

    • Author(s)
      Miyashita Kazuya、Kitajima Kenji、Goyama Susumu、Kitamura Toshio、Hara Takahiko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 3 Pages: 2310-2316

    • DOI

      10.1016/j.bbrc.2017.12.135

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CXCL14 Acts as a Specific Carrier of CpG DNA into Dendritic Cells and Activates Toll-like Receptor 9-mediated Adaptive Immunity2017

    • Author(s)
      Tanegashima Kosuke、Takahashi Rena、Nuriya Hideko、Iwase Rina、Naruse Naoto、Tsuji Kohei、Shigenaga Akira、Otaka Akira、Hara Takahiko
    • Journal Title

      EBioMedicine

      Volume: 24 Pages: 247-256

    • DOI

      10.1016/j.ebiom.2017.09.012

    • NAID

      120006941113

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [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.
    • Journal Title

      Stem Cell Reports.

      Volume: 9(4) Issue: 4 Pages: 1180-1191

    • DOI

      10.1016/j.stemcr.2017.08.012

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice.2017

    • Author(s)
      Tanegashima, Y. Sato-Miyata, M. Funakoshi, Y. Nishito, T. Aigaki, and T. Hara.
    • Journal Title

      Genes to Cells

      Volume: 22 Issue: 1 Pages: 71-83

    • DOI

      10.1111/gtc.12456

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Efficient production of platelets from mouse embryonic stem cells by enforced expression of Gata2 in late hemogenic endothelial cells.2016

    • Author(s)
      M. Kawaguchi, K. Kitajima, M. Kanokoda, H. Suzuki, K. Miyashita, M. Nakajima, H. Nuriya, K. Kasahara, and T. Hara.
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 474 Issue: 3 Pages: 462-468

    • DOI

      10.1016/j.bbrc.2016.04.140

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Highly Efficient Transfer of Chromosomes to a Broad Range of Target Cells Using Chinese Hamster Ovary Cells Expressing Murine Leukemia Virus-Derived Envelope Proteins.2016

    • Author(s)
      Suzuki T, Kazuki Y, Oshimura M, Hara T.
    • Journal Title

      PLoS One.

      Volume: 11 Issue: 6 Pages: e0157187-e0157187

    • DOI

      10.1371/journal.pone.0157187

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 転写因子Gata2の赤血球巨核球誘導ドメインの同定.2018

    • Author(s)
      北島健二, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] DDX1の欠損はp53経路を介してマウス胚性幹細胞の増殖を抑制する.2018

    • Author(s)
      鈴木輝彦, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 転写因子Gata4によるマウスES細胞から原始内胚葉系細胞への分化誘導メカニズム.2018

    • Author(s)
      田畑陽美, 北島健二, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] CpG DNA/CXCL14複合体に対する候補受容体の発現クローニング.2018

    • Author(s)
      三井貴洋, 種子島幸祐, 成瀬公人, 重永 章, 大髙 章, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] CXCL14とCpG DNAの相互作用によるTLR9活性化の特異性と責任領域の解析.2018

    • Author(s)
      岩瀬璃奈, 成瀬公人, 種子島幸祐, 重永 章, 大髙 章, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 急性Tリンパ芽球性白血病細胞の増殖を特異的に抑える化合物の標的分子探索.2018

    • Author(s)
      八木拓哉, 鉢呂佳史, 吉田千紘, 西藤泰昌, 武智あづさ, 宮下和也, 牧 昌次郎, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 寿命死直前のショウジョウバエで発現変動する遺伝子群の同定.2018

    • Author(s)
      武智あづさ, 大沼康平, 種子島幸祐, 相垣敏郎, 西藤泰昌, 原 孝彦.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 急性Tリンパ芽球性白血病細胞の増殖を特異的に抑える低分子化合物の創出.2018

    • Author(s)
      鉢呂佳史, 吉田千紘, 宮下和也, 八木拓哉, 武智あづさ, 原 孝彦, 牧 昌次郎.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 急性赤白血病細胞の増殖を抑制する低分子化合物の創出.2018

    • Author(s)
      吉田千紘, 武智あづさ, 鉢呂佳史,八木拓哉, 原 孝彦, 牧 昌次郎.
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Multiple functions of CXCL14 in the CpG DNA transport into dendritic cells/macrophages for modulating Toll-like receptor 9 signaling.2018

    • Author(s)
      Takahiko Hara.
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 急性Tリンパ芽球性白血病T-ALLに対する新しい治療薬の開発研究.2017

    • Author(s)
      原 孝彦
    • Organizer
      老年者造血器疾患研究会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] マウスES細胞から血液細胞への分化における転写因子Gata2のドメイン特異的な機能.2017

    • Author(s)
      北島健二, 鹿子田 真衣, 原 孝彦.
    • Organizer
      第40回日本分子生物学会年会ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] 新しいゲノム編集技術によるDdx1遺伝子のコンディショナルノックアウト.2017

    • Author(s)
      鈴木 輝彦, 田中貴代子, 原 孝彦.
    • Organizer
      第40回日本分子生物学会年会ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] DDX1過剰発現とPTPN23欠損による精巣腫瘍発症モデル.2017

    • Author(s)
      池田成海, 田中貴代子, 原 孝彦.
    • Organizer
      第40回日本分子生物学会年会ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] ヒトiPS細胞の血液細胞分化に対するLIMホメオドメイン転写因子Lhx2の機能.2017

    • Author(s)
      高橋佑奈, 北島健二, 原 孝彦.
    • Organizer
      第40回日本分子生物学会年会ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] ハダカデバネズミ皮膚線維芽細胞株の樹立とゲノム編集.2017

    • Author(s)
      中曽根茉季, 鈴木輝彦, 三浦恭子, 原 孝彦.
    • Organizer
      第40回日本分子生物学会年会ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] A Novel Function of a CXC-type Chemokine CXCL14 as a Specific Carrier of CpG DNA into Dendritic Cells for Activating Toll-like Receptor 9-mediated Adaptive Immunity.2016

    • Author(s)
      T. Hara, K. Tanegashima, R. Takahashi, H. Nuriya, N. Naruse, K. Tsuji, A. Shigenaga, and A. Otaka.
    • 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
      2016 Annual Research Report
    • Int'l Joint Research
  • [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
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CXCケモカインCXCL14はCpG DNAに結合し、Toll-like receptor 9シグナルを活性化する.2016

    • Author(s)
      種子島幸祐, 髙橋伶奈, 塗屋秀子, 成瀬公人, 辻耕平, 重永 章, 大髙 章, 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
      2016 Annual Research Report
  • [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
      2016 Annual Research Report
  • [Remarks] 公益財団法人東京都医学総合研究所 幹細胞プロジェクト

    • Related Report
      2018 Annual Research Report
  • [Remarks] 公益財団法人東京都医学総合研究所 幹細胞プロジェクト

    • Related Report
      2017 Annual Research Report
  • [Remarks] 公益財団法人東京都医学総合研究所 幹細胞プロジェクト

    • URL

      http://www.igakuken.or.jp/stem-cell/

    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 白血病治療用医薬組成物2018

    • Inventor(s)
      原 孝彦, 宮下和也, 牧 昌次郎, 他4名
    • Industrial Property Rights Holder
      公益財団法人東京都医学総合研究所
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] ケモカインCXCL14を利用した自然免疫活性化アジュバント2017

    • Inventor(s)
      種子島幸祐, 原 孝彦, 重永 章, 大高 章, 高橋伶奈.
    • Industrial Property Rights Holder
      公益財団法人東京都医学総合研究所
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] ケモカインCXCL14を利用した自然免疫活性化アジュバント2016

    • Inventor(s)
      種子島幸祐, 高橋伶奈, 原孝彦, 辻耕平, 重永章, 大高章
    • Industrial Property Rights Holder
      公益財団法人東京都医学総合研究所
    • Industrial Property Rights Type
      特許
    • Filing Date
      2016-04-28
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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