Analysis of proliferation and differentiation of human embryonic stem cells and research for clinical application

2009 Fiscal Year Final Research Report

• Project/Area Number: 19109006
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: NAKAHATA Tatsutoshi Kyoto University, 物質-細胞統合システム拠点, 特定拠点教授 (20110744)
• Co-Investigator(Renkei-kenkyūsha): HEIKE Toshio 京都大学, 医学研究科, 教授 (90190173) ; UMEDA Katsutsugu 京都大学, 医学研究科, 助手 (80397538) ; SAITOH Megumu 京都大学, 物質-細胞統合システム拠点, 特定拠点助教 (90535486)
• Project Period (FY): 2007 – 2009
• Keywords: ES細胞 / ヒト / 再生医療 / 幹細胞 / NOGマウス

Research Abstract

We attempt to discover the culture system for generation of desired lineage-specific stem cells from human ES cells and succeeded in generating progenitor cells for hematopoietic cells, endothelial cells, skeletal muscle, cardiomyocytes and neural cells.
VEGFR-2(+)CD34(+) cells are identified as a candidate of primate hemangioblasts. We established a novel protocol to derive myogenic precursors from murine ES/iPS cells with a monoclonal antibody SM/C-2.6 that recognizes quiescent satellite cells. SM/C-2.6-positive cells are highly myogenic and efficiently differentiate into myofibers both in vitro and in vivo. We recently developed culture system for skeletal muscle cells from human ES cells.
Recently, we developed an excellent humanized model mouse, NOG mouse, in which successful engraftment was achieved even if small number of CD34^+ cells were transplanted into the mice. In this study we confirmed that NOG mouse was useful for evaluation of ES/iPS cell-derived tissue specific stem cells.

Research Products

• [Journal Article] Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis. (2009)
  • Author(s): Okafuji I, Nishikomori R, Kanazawa N, Kambe N, Fujisawa A, Yamazaki S, Saito M, Yoshioka T, Kawai T, Sakai H, Tanizaki H, Heike T, Miyachi Y, Nakahata T.
  • Journal Title: Arthritis Rheum. 60 Pages: 242-50
• [Journal Article] Generation of transplantable, functional satellite-like cells from mouse embryonic stem cells. (2009)
  • Author(s): Chang H, Yoshimoto M, Umeda K, Iwasa T, Mizuno Y, Fukada SI, Yamamoto H, Motohashi N, Suzuki YM, Takeda S, Heike T, Nakahata T.
  • Journal Title: FASEB J. 23 Pages: 1907-1919
• [Journal Article] AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist. (2009)
  • Author(s): Fukushima-Shintani M, Suzuki KI, Iwatsuki Y, Abe M, Sugasawa K, Hirayama F, Kawasaki T, Nakahata T.
  • Journal Title: Eur J Haematol. 82 Pages: 247-254
• [Journal Article] Direct hematological toxicity and illegitimate chromosomal recombination caused by the systemic activation of CreERT2。. (2009)
  • Author(s): Higashi A.Y., Ikawa T, Muramatsu M, Economides A.N., Niwa A, Okuda T, Murphy AJ., Rojas J, Heike T, Nakahata T, Kawamoto H, Kita T, Yanagita M.
  • Journal Title: J Immunol. 182 Pages: 5633-5640
• [Journal Article] The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. (2009)
  • Author(s): Yokoo N., Baba S., Kaichi S., Niwa A., Mima T., Doi H., Yamanaka S., Nakahata T., Heike T.
  • Journal Title: Biochem. Biophys. Res. Com. 387 Pages: 482-488
• [Journal Article] Selective infection of CD(4)+ effector memory T lymphocytes leads to preferential depletion of memory T lymphocytes in R5 HIV-infected humanized NOD/SCID/IL-2Rγnull mice. (2009)
  • Author(s): Nie C, Sato K, Misawa N, Kitayama H, Fujino H, Hiramatsu H, Heike T, Nakahata T, Tanaka Y, Ito M, Koyanagi Y
  • Journal Title: Virology 394 Pages: 64-72
• [Journal Article] Frequent inactivation of A20 in B-cell lymphomas. (2009)
  • Author(s): Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, Asakura Y, Muto S, Tamura A, Iio M, Akatsuka Y, Hayashi Y, Mori H, Igarashi T, Kurokawa M, Chiba S, Mori S, Ishikawa Y, Okamoto K, Tobinai K, Nakagama H, NakahatKato M, Sanada M, Kato I, Sato Y, Ta
  • Journal Title: Nature 459 Pages: 712-716
• [Journal Article] Orderly Hematopoietic Development of Induced Pluripotent Stem Cells via Flk-1+ Hemoangiogenic Progenitors. (2009)
  • Author(s): Niwa A., Umeda K., Chang H., Saito M., Okita K., Takahashi K., Nakagawa M., Yamanaka S., Nakahata T., Heike T
  • Journal Title: J. Cell. Physiol. 221 Pages: 367-377
• [Journal Article] Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. (2009)
  • Author(s): Miyara M., Yoshioka Y., Kitoh A., Shima T., Wing K., Niwa A., Perizot C., Taflin C., Heike T., Valeyre D., Mathian A., Nakahata T., Yamaguchi T., Nomura T., Ono M., Amoura Z., Gorochov G., Sakaguchi S.
  • Journal Title: Immunity 30 Pages: 899-911
• [Journal Article] I. 造血幹細胞1. iPS細胞からの造血分化. (2009)
  • Author(s): 丹羽明、中畑龍俊
  • Journal Title: Annual Review血液2009 40551 Pages: 1
• [Journal Article] 対外増幅造血細胞移植. (2009)
  • Author(s): 伊藤仁也, 中畑龍俊
  • Journal Title: 医学のあゆみ 229(9) Pages: 786-792
• [Journal Article] 疾患特異的iPS細胞. (2009)
  • Author(s): 中畑龍俊
  • Journal Title: 学術の動向 14(9) Pages: 78-83
• [Journal Article] to preferential depletion of memory T lymphocytes in R5 HIV-infected humanized NOD/SCID/IL-2Rγnull mice. (2009)
  • Author(s): KamitsujiY, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y
  • Journal Title: Virology 394 Pages: 64-72
• [Journal Article] Direct development of functionary mature tryptase/ chymase double-positive connective tissue-type mast cells from primate embryonic stem cells. (2008)
  • Author(s): Ma F, Kambe N, Dan W, Shinoda G, Fujino H, Umeda K, Fujisawa A, Ma L, Suemori H, Nakatsuji N, Miyachi Y, Torii R, Tsuji K, Heike T, Nakahata T
  • Journal Title: Stem Cells 26 Pages: 706-714
• [Journal Article] NOD/Shi-scid IL2rγnull (NOG)Mice More Appropriate for Humanized Mouse Models. (2008)
  • Author(s): Ito M, Kobayashi K, Nakahata T
  • Journal Title: Curr. Top. Microbiol. Immunol. 324 Pages: 54-76
• [Journal Article] Generatuion of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis. (2008)
  • Author(s): Ma F, Ebihara Y, Umeda K, Sakai H, Hanada S, Hong Z, Zaike Y, Tsuchida E, Nakahata T, Nakauchi H, Tsuji K
  • Journal Title: PNAS 105(35) Pages: 13087-13092
• [Journal Article] Side population cells contribute to the genesis of human endometrium. (2008)
  • Author(s): Tsuji S, Yoshimoto M, Takahashi K, Noda Y, Nakahata T, Heike T
  • Journal Title: Fertility and Sterility 90 Pages: 1528-1537
• [Journal Article] Sca-1+ endothelial cells (SPECs) reside in the portal area of the liver and contribute to rapid recovery from acute liver disease. (2008)
  • Author(s): Tsuchiya A., Heike T., Baba S., Fujino H., Umeda K., Matsuda Y., Nomoto M., Ichida T., Aoyagi Y., Nakahata T.
  • Journal Title: Biochem. Biophys. Res. Com. 365 Pages: 595-601
• [Journal Article] Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. (2008)
  • Author(s): Saito M., Nishikomori R., Kambe N., Fujisawa A., Tanizaki H., Takeichi K., Imagawa T., Iehara T., Takada H., Matsubayashi T., TanakaH., Kawashima K., Kagami S., Kawai T., Okafuji I., Yoshioka T., Adachi S., Heike T., Miyachi Y., Nakahata T.
  • Journal Title: Blood 111 Pages: 2132-2141
• [Journal Article] Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality. (2008)
  • Author(s): Yamanaka Y., Kumada T., Heike T., Shibata M., Takaoka Y., Kitano A., Shiraishi K., Kato T., Nagato M., Okawa K., Furushima K., Nakao K., Aizawa S., Nakamura Y., Taketo M.M. Nakahata T.
  • Journal Title: Mech. Develop. 125 Pages: 4441-450
• [Journal Article] 幹細胞の臨床応用とその課題. (2008)
  • Author(s): 中畑龍俊
  • Journal Title: 日本臨床 66(5) Pages: 831-840
• [Journal Article] 造血幹細胞. 進みつづける細胞移植治療の実際上巻ー再生医療の実現に向けた科学・技術と周辺要素の理解ー (2008)
  • Author(s): 中畑龍俊
  • Journal Title: 遺伝子医学MOOK別冊メディカルドゥ 60-66
• [Journal Article] Isolation and characterization of bone marrow-derived mesenchymal progenitor cells with myogenic and neuronal properties. (2007)
  • Author(s): Shiota M, Heike T, Haruyama M, Baba S, Tsuchiya A, Fujino H, Kobayashi H, Umeda K, Yoshimoto M, Nakahata T
  • Journal Title: Exp Cell Res. 313(5) Pages: 1008-1023
• [Journal Article] α4-Integrin+ endothelium deriverd from primate embryonic stem cells generates primitive and definitive hematopoietic cells. (2007)
  • Author(s): Shinoda G, Umeda K, Heike T, Arai M, Niwa A, Ma F, Suemori H, Luo HY, Chui DH, Torii R, Shibuya M, Nakatsuji N, Nakahata T
  • Journal Title: Blood 109(6) Pages: 2406-2415
• [Journal Article] Generation of Cardiac and Endothelial Cells from Neonatal Mouse Testis-Derived Multipotent Germline Stem Cells. (2007)
  • Author(s): Baba S, Heike T, Umeda K, Iwasa T, Kaichi S, Hiraumi T, Doi H, Yoshimoto M, Kanatsu-Shinohata M, Shinohara T, Nakahata T
  • Journal Title: Stem Cells 25 Pages: 1375-1383
• [Journal Article] Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells. (2007)
  • Author(s): Fujisawa A, Kambe N, Saito M, Nishikomori R, Tanizaki H, Kanazawa N, Adachi S, Heike T, Sagara J, Suda T, Nakahata T, Miyachi Y
  • Journal Title: Blood 109(7) Pages: 2903-2911
• [Journal Article] Long-term culture of postnatal mouse hepatic stem/ progenitor cells and their relative development hierarchy. (2007)
  • Author(s): Tsuchiya A, Heike T, Baba S, Fujino H, Umeda K, Matsuda Y, Nomoto M, Ichida T, AoyagiY, Nakahata T
  • Journal Title: Stem Cells 25 Pages: 895-902
• [Journal Article] Flk1+ cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model. (2007)
  • Author(s): Baba S, Heike T, Yoshimoto M, Umeda K, Doi H, Iwasa T, Lin X, Matsuoka S, Komeda M, Nakahata T
  • Journal Title: Cardiiovascular Res. 76 Pages: 119-131
• [Journal Article] Characterization of side-population cells in human normal endometrium. (2007)
  • Author(s): Kato K, Yoshimoto M, Kato K, Adachi S, Yamayoshi A, ArimaT, Asanoma K, Kyo S, Nakahata T, Wake N
  • Journal Title: Human Reproduction 22(5) Pages: 1214-1223
• [Journal Article] Notch ligand Delta-1 differentially modulates the effects of gp130 activation on interleukin-6 receptorα-positive and-negative human hematopoietic progenitors. (2007)
  • Author(s): Yamamura K, Ohishi K, Katayama N, Kato K, Shibasaki T, Sugimoto Y, Miyata E, Shiku H, Masuya M, Nishioka J, Nobori T, Nishikawa M, Yoshimasa I, Hiramatsu H, Nakahata T
  • Journal Title: Cancer Sci 98(10) Pages: 1597-1603
• [Journal Article] Human cord blood CD34+ cells develop into hepatocytes in the livers of NOD/SCID/gcnull mice through cell fusion. (2007)
  • Author(s): Fujino H, Hiramatsu H, Tsuchiya A, Niwa A, Noma H, Shiota M, Umeda K, Yoshimoto M, Ito M, Heike T, Nakahata T.
  • Journal Title: FASEB J. 21 Pages: 3499-3510
• [Journal Article] Novel method for efficient production of multipotential hematopoietic progenitors from human embryonic stem cells. (2007)
  • Author(s): Ma F., Wang D., Hanada S., Ebihara Y., Kawasaki H., Zaike Y., Heike T., Nakahata T., Tsuji K.
  • Journal Title: Int. Hematol. 85 Pages: 371-379
• [Journal Article] Efficient Assay for Evaluating human thrombopoiesis using NOD/SCID mice transplanted with cord blood CD34+ cells. (2007)
  • Author(s): Suzuki K, Hiramatsu H, Fukushima-Shintani M, Heike T, Nakahata T.
  • Journal Title: Eur J Haematol 78 Pages: 123-130
• [Journal Article] B cell potetial can be obtained from pre-circulatory yolk sac, but with low frequency. (2007)
  • Author(s): Sugiyama D, Ogawa M, Nakao K, Osumi N, Nishikawa S, Nishikawa S, Arai K, Nakahata T, Tsuji K
  • Journal Title: Dev. Biol. 301 Pages: 53-61
• [Journal Article] 血球系の再生医療. (2007)
  • Author(s): 中畑龍俊, 梅田雄嗣
  • Journal Title: Medical Science Digest 33(14) Pages: 20-24
• [Journal Article] ヒトes細胞を用いた造血幹細胞や神経幹細胞への分化誘導. (2007)
  • Author(s): 平家俊男, 梅田雄嗣, 加藤竹雄, 中畑龍俊
  • Journal Title: 医学のあゆみ 220(2) Pages: 186-190
• [Journal Article] Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells.
  • Author(s): Mizuno Y., Chang H., Umeda K., Niwa A., IwasaT., Awaya T., Fukada S., Hiroshi Yamamoto H., Yamanaka S., Nakahata T., Heike T.
  • Journal Title: FASEB J. (in press)
• [Presentation] Future of regenerative medicine with various stem cells. (2009)
  • Author(s): Tatsutoshi Nakahata
  • Organizer: The 3rd International Symposium of Lysosomal Storage Deseases
  • Place of Presentation: 名古屋能楽堂名古屋市
  • Year and Date: 20090926-20090927
• [Presentation] 造血幹細胞を用いた再生医療 (2009)
  • Author(s): 中畑龍俊
  • Organizer: 第27回日本医学会総会
  • Place of Presentation: 大阪
  • Year and Date: 20090406-20090408
• [Presentation] Special lecture: Proliferation and Differentiation of Various Stem Cells in vitro and in vivo. (2008)
  • Author(s): Tatsutoshi Nakahata
  • Organizer: Advances in Neuroblastoma Research 2008国際神経芽腫学会
  • Place of Presentation: Makuhari Messe International Conference Hall Chiba
  • Year and Date: 20080521-20080524
• [Remarks] ホームページ等
  • URL: http://www.cira.kyoto-u.ac.jp/j/research/nakahata-summary.html
• [Patent(Industrial Property Rights)] 多能性幹細胞からの肥満細胞の製造方法 (2009)
  • Inventor(s): Tatsutoshi Nakahata, Kohichiro Tsuji, Feng MA
  • Industrial Property Rights Holder: Kyoto University
  • Industrial Property Number: 海外出願・61/240,376
  • Filing Date: 2009-09-08
• [Patent(Industrial Property Rights)] 多能性幹細胞から中胚葉細胞の分化誘導法
  • Inventor(s): 丹羽明, 中畑龍俊
  • Industrial Property Rights Holder: Kyoto University
  • Industrial Property Number: 海外出願・61/315,170