Development of novel differentiation induction system of hematopoietic stem cells from human induced pluripotent stem cells

• Project/Area Number: 24591415
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: KITAJIMA Kenji 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)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: iPS細胞 / 造血幹細胞 / ホメオボックス / 細胞分化 / 試験管内分化誘導 / 転写因子 / 再生医療 / 血液細胞

Outline of Final Research Achievements

We previously demonstrated that hematopoietic stem cell (HSC)-like cells were obtained from mouse induced pluripotent stem cells (iPSCs). When mouse iPSCs are differentiated into hemogenic endothelial cells (HECs) and a transcription factor Lhx2, known to induce ex vivo amplification of adult HSCs, is introduced, HSC-like cells are differentiated. Based on this finding, we challenged to induced HSCs from human iPSCs. First, we established an efficient in vitro hematopoietic differentiation induction system from human iPSCs. We found that a GSK3beta inhibitor greatly improved hematopoietic differentiation from human iPSCs. Using this method, we carried out enforced expression of Lhx2 into human iPSC-derived HECs. However, HSC-like cells were hardly obtained.

Research Products

• [Journal Article] LIM homeobox transcription factor Lhx2 inhibits skeletal muscle differentiation in part via transcriptional activation of Msx1 and Msx2. (2015)
  • Author(s): Kodaka Y, Tanaka K, Kitajima K, Tanegashima K, Matsuda R, Hara T.
  • Journal Title: Exp Cell Res Volume: 331 Pages: 309-319
  • Peer Reviewed
• [Journal Article] Endothelial cell-specific expression of roundabout 4 is regulated by differential DNA methylation of the proximal promoter. (2014)
  • Author(s): Okada Y, Funahashi N, Tanaka T, Nishiyama Y, Yuan L, Shirakura K, Turjman AS, Kano Y, Naruse H, Suzuki A, Sakai M, Zhixia J, Kitajima K, Ishimoto K, Hino N, Kondoh M, Mukai Y, Nakagawa S, Garcia-Cardena G, Aird WC, Doi T.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 34 Pages: 1531-1538
  • Peer Reviewed
• [Journal Article] Molecular functions of the LIM-homeobox transcription factor Lhx2 in hematopoietic progenitor cells derived from mouse embryonic stem cells. (2013)
  • Author(s): K. Kitajima, M. Kawaguchi, M. Iacovino, M. Kyba, and T. Hara
  • Journal Title: Stem Cells Volume: 31 Issue: 12 Pages: 2680-2689
  • DOI: 10.1002/stem.1500
  • Peer Reviewed
• [Journal Article] Tumor suppressive function of PTPN23 in testicular germ cell tumors is lost upon overexpression of miR-142-3p (2013)
  • Author(s): Kiyoko Tanaka
  • Journal Title: Journal of Biological Chemistry Volume: - Issue: 33 Pages: 23990-23999
  • DOI: 10.1074/jbc.m113.478891
  • Peer Reviewed
• [Journal Article] Embryonic stem cell differentiation system for evaluating gene functions involved in physiological megakaryocytic differentiation. (2012)
  • Author(s): Okada Y, Yonekura M, Watanabe M, Nakai T, Wakimura A, Shimizu M, Kamikawa Y, Kitayama M, Kitajima K, Aird WC, Doi T.
  • Journal Title: Biochem Biophys Res Commun Volume: 419 Pages: 477-481
  • Peer Reviewed
• [Journal Article] ES細胞・iPS細胞から機能的な血液細胞を作り出す方法． (2012)
  • Author(s): 原 孝彦，北島 健二
  • Journal Title: 実験医学 Volume: 30 Pages: 1671-1676
• [Presentation] 転写因子Lhx2による多能性幹細胞から長期骨髄再建能を有する造血幹細胞様細胞への誘導 (2014)
  • Author(s): 北島健二，川口真実，宮下和也，鹿子田真衣，中島 鞠乃，原孝彦.
  • Organizer: 第 37 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: 2014-11-25
• [Presentation] Transcription factor Lhx2 inhibits proliferation of T-cell acute lymphoblastic leukemia-derived cells. (2014)
  • Author(s): Miyashita K, Kitajima K, Hara T.
  • Organizer: The 12th Stem Cell Research Symposium
  • Place of Presentation: 九州大学・百年講堂 （福岡県・福岡市）
  • Year and Date: 2014-05-30 – 2014-05-31
• [Presentation] 転写制御因子Lhx2は急性Tリンパ芽球性白血病細胞の増殖を抑制する (2013)
  • Author(s): 宮下 和也，北島 健二，原 孝彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Gata2はhemogenic endothelial cells からの血液細胞出芽を促進する (2013)
  • Author(s): 川口 真実，北島 健二，原 孝彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Lhx2は筋脱分化因子Msx1, Msx2の発現を制御する (2013)
  • Author(s): 小高 悠作，田中 貴代子，北島 健二，松田 良一，原 孝彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] In vitro induction of HSC-like cells from mouse ESCs/iPSCs by a transcription factor Lhx2 (2013)
  • Author(s): Kitajima K, Kawaguchi M, Miyashita K, Hara T
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 札幌
• [Presentation] Molecular functions of the LIM-homeobox transcription factor Lhx2 in hematopoietic stem-like cell differentiation from mouse embryonic stem cells (2013)
  • Author(s): Kitajima K, Kawaguchi M, Iacovino M, Kyba M, Hara T
  • Organizer: The 11th Stem Cell Research Sympojium
  • Place of Presentation: 東京
• [Presentation] Molecular functions of the LIM-homeobox transcription factor Lhx2 in hematopoietic stem­like cell differentiation from mouse embryonic stem cells. (2013)
  • Author(s): Kitajima K, Kawaguchi M, Iacovino M, Kyba M, Hara T.
  • Organizer: The 11th Stem Cell Research Symposium
  • Place of Presentation: Tokyo
• [Presentation] Enforced expression of Lhx2 enhances the differentiation of CD41+ hematopoietic precursors from mouse ES cells. (2012)
  • Author(s): Kawaguchi M, Kitajima K, Kyba M, Hara T.
  • Organizer: The 35th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Fukuoka
• [Presentation] Induction of hematopoietic stem-like cells from mouse pluripotent stem cells by LIM-homeobox transcription factor Lhx2. (2012)
  • Author(s): Kitajima K, Kawaguchi M, Momiyama K, Kyba M, Hara T.
  • Organizer: The 35th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Fukuoka
  • Invited
• [Presentation] Underlying mechanisms of the in vitro induction of hematopoietic stem cell-like cells from mouse embryonic stem cells by LIM-homeobox transcription factor, Lhx2. (2012)
  • Author(s): Kitajima K, Kyba M, Hara T.
  • Organizer: International Society for Stem Cell Research 10th Annual Meeting
  • Place of Presentation: Yokohama