骨髄造血幹細胞ニッチの構造と機能の解明

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24249056
• Research Institution: The University of Tokyo
• Principal Investigator: 中内 啓光 東京大学, 医科学研究所, 教授 (40175485)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 骨髄ニッチ / TGF-beta / 休眠状態

Outline of Annual Research Achievements

本申請課題である骨髄造血幹細胞ニッチの構造と機能の解明における研究実績を以下に記述する。

我々は骨髄ニッチ細胞を基本から見直し、以前にTGF-betaシグナルが造血幹細胞のニッチ因子であることを同定した（Yamazaki et al.,2009. Blood）その研究成果により骨髄に存在する非髄鞘シュワン細胞がTGF-betaを活性化し造血幹細胞に受け渡していることで造血幹細胞の休眠状態と未分化性を維持しており、骨髄ニッチを構成する１つの細胞であることを報告した（Yamazaki et al.,2011. Cell）。またヒト骨髄環境においてもマウスと同様な機能が存在することも確認している（Kimura et al., Unpublished data）。また造血幹細胞を制御している細胞が神経系細胞であるために概日時計に関する造血幹細胞の表現形を解析した。その結果、概日遺伝子であるBmal1を欠損したマウスにおいても造血幹細胞の表現形は見いだせなかったために概日時計と造血幹細胞における関係性がないということを詳細に示した（Ieyasu et al., 2013 JNR）。

さらには、我々は骨髄ニッチと造血幹細胞の深い理解と技術を得たこともあり、iPS細胞からの造血幹細胞の分化誘導法にも成功している。通常は生体外においてiPS細胞からの造血幹細胞の誘導を目指すことが多い。しかし、我々はiPS細胞を生体内に投与しテラトーマを作製し生体内で造血幹細胞の発生を模倣することで、移植可能かつ機能的な造血幹細胞がマウス、ヒトともに誘導可能であることを証明した（Suzuki et al., 2013 Mol Ther）。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Effect of donor chimerism to reduce the level of glycosaminoglycans following bone marrow transplantation in a murine model of mucopolysaccharidosis type II (2015)
  • Author(s): Yokoi K, Akiyama K, Kaneshiro E, Higuchi T, Shimada Y, Kobayashi H, Akiyama M, Otsu M, Nakauchi H, Ohashi T, Ida H
  • Journal Title: Journal of inherited metabolic disease Volume: 38 Pages: 333-40
  • DOI: 10.1007/s10545-014-9800-x
  • Peer Reviewed
• [Journal Article] Screening of Drugs to Treat 8p11 Myeloproliferative Syndrome Using Patient-Derived Induced Pluripotent Stem Cells with Fusion Gene CEP110-FGFR1 (2015)
  • Author(s): Yamamoto S, Otsu M, Matsuzaka E, Konishi C, Takagi H, Hanada S, Mochizuki S, Nakauchi H, Imai K, Tsuji K, Ebihara Y
  • Journal Title: PloS one Volume: 10 Pages: e0120841
  • DOI: 10.1371/journal.pone.0120841
  • Peer Reviewed / Open Access
• [Journal Article] Circulating cells contribute to cardiomyocyte regeneration after injury (2015)
  • Author(s): Wu JM, Hsueh YC, Ch'ang HJ, Luo CY, Wu LW, Nakauchi H, Hsieh PC
  • Journal Title: Circulation research Volume: 116 Pages: 633-41
  • DOI: 10.1161/CIRCRESAHA.116.304564
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking (2015)
  • Author(s): Sato A, Nishida C, Sato-Kusubata K, Ishihara M, Tashiro Y, Gritli I, Shimazu H, Munakata S, Yagita H, Okumura K, Tsuda Y, Okada Y, Tojo A, Nakauchi H, Takahashi S, Heissig B, Hattori K
  • Journal Title: Leukemia Volume: 29 Pages: 145-56
  • DOI: 10.1038/leu.2014.151
  • Peer Reviewed
• [Journal Article] Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse mode (2015)
  • Author(s): Nakauchi Y, Yamazaki S, Napier SC, Usui J, Ota Y, Takahashi S, Watanabe N, Nakauchi H
  • Journal Title: Experimental hematology Volume: 43 Pages: 79-88
  • DOI: 10.1016/j.exphem.2014.10.008
  • Peer Reviewed / Open Access
• [Journal Article] Quantification of adult T-cell leukemia/lymphoma cells using simple four-color flow cytometry (2015)
  • Author(s): Ishigaki T, Zaike Y, Nojima M, Kobayashi S, Ohno N, Uchimaru K, Tojo A, Nakauchi H, Watanabe N.
  • Journal Title: Clinical chemistry and laboratory medicine : CCLM / FESCC Volume: 53 Pages: 85-93
  • DOI: 10.1515/cclm-2014-0183
  • Peer Reviewed
• [Journal Article] T-cell-restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung (2015)
  • Author(s): Iriguchi S, Kikuchi N, Kaneko S, Noguchi E, Morishima Y, Matsuyama M, Yoh K, Takahashi S, Nakauchi H, Ishii Y
  • Journal Title: Blood Volume: 125 Pages: 370-82
  • DOI: 10.1182/blood-2014-05-575225
  • Peer Reviewed / Open Access
• [Journal Article] Bone marrow Schwann cells induce hematopoietic stem cell hibernation (2014)
  • Author(s): Yamazaki S, Nakauchi H
  • Journal Title: International journal of hematology Volume: 99 Pages: 695-8
  • DOI: 10.1007/s12185-014-1588-9
  • Peer Reviewed / Open Access
• [Journal Article] Five-lineage clonal analysis of hematopoietic stem/progenitor cells (2014)
  • Author(s): Yamamoto R, Morita Y, Nakauchi H
  • Journal Title: Methods in molecular biology Volume: 1185 Pages: 237-45
  • DOI: 10.1007/978-1-4939-1133-2_16
  • Peer Reviewed
• [Journal Article] Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients (2014)
  • Author(s): Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Yuasa S, Yamazaki S, Nishimura T, Sadahira K, Fukuda K, Okano H, Nakauchi H, Morita Y, Matsumura I, Kudo K, Ito E, Ebihara Y, Tsuji K, Harada Y, Harada H, Okamoto S, Nakajima H
  • Journal Title: Leukemia Volume: 28 Pages: 2344-54
  • DOI: 10.1038/leu.2014.136
  • Peer Reviewed
• [Journal Article] Multicolor staining of globin subtypes reveals impaired globin switching during erythropoiesis in human pluripotent stem cells (2014)
  • Author(s): Ochi K, Takayama N, Hirose S, Nakahata T, Nakauchi H, Eto K
  • Journal Title: Stem cells translational medicine Volume: 3 Pages: 792-800
  • DOI: 10.5966/sctm.2013-0216
  • Peer Reviewed
• [Journal Article] Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells (2014)
  • Author(s): Nakamura S, Takayama N, Hirata S, Seo H, Endo H, Ochi K, Fujita K, Koike T, Harimoto K, Dohda T, Watanabe A, Okita K, Takahashi N, Sawaguchi A, Yamanaka S, Nakauchi H, Nishimura S, Eto K
  • Journal Title: Cell stem cell Volume: 14 Pages: 535-48
  • DOI: 10.1016/j.stem.2014.01.011
  • Peer Reviewed
• [Journal Article] The TIF1beta-HP1 system maintains transcriptional integrity of hematopoietic stem cells (2014)
  • Author(s): Miyagi S, Koide S, Saraya A, Wendt GR, Oshima M, Konuma T, Yamazaki S, Mochizuki-Kashio M, Nakajima-Takagi Y, Wang C, Chiba T, Kitabayashi I, Nakauchi H, Iwama A
  • Journal Title: Stem cell reports Volume: 2 Pages: 145-52
  • DOI: 10.1016/j.stemcr.2013.12.008
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia (2014)
  • Author(s): Matsunawa M, Yamamoto R, Sanada M, Sato-Otsubo A, Shiozawa Y, Yoshida K, Otsu M, Shiraishi Y, Miyano S, Isono K, Koseki H, Nakauchi H, Ogawa S
  • Journal Title: Leukemia Volume: 28 Pages: 1844-50
  • DOI: 10.1038/leu.2014.73
  • Peer Reviewed
• [Journal Article] Stage-specific roles for CXCR4 signaling in murine hematopoietic stem/progenitor cells in the process of bone marrow repopulation (2014)
  • Author(s): Lai CY, Yamazaki S, Okabe M, Suzuki S, Maeyama Y, Iimura Y, Onodera M, Kakuta S, Iwakura Y, Nojima M, Otsu M, Nakauchi H
  • Journal Title: Stem cells Volume: 32 Pages: 1929-42
  • DOI: 10.1002/stem.1670
  • Peer Reviewed
• [Journal Article] Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies (2014)
  • Author(s): Kazuki Y, Yakura Y, Abe S, Osaki M, Kajitani N, Kazuki K, Takehara S, Honma K, Suemori H, Yamazaki S, Sakuma T, Toki T, Shimizu R, Nakauchi H, Yamamoto T, Oshimura M
  • Journal Title: Scientific reports Volume: 4 Pages: 6136
  • DOI: 10.1038/srep06136
  • Peer Reviewed / Open Access
• [Journal Article] Gene targeting study reveals unexpected expression of brain-expressed X-linked 2 in endocrine and tissue stem/progenitor cells in mice (2014)
  • Author(s): Ito K, Yamazaki S, Yamamoto R, Tajima Y, Yanagida A, Kobayashi T, Kato-Itoh M, Kakuta S, Iwakura Y, Nakauchi H, Kamiya A
  • Journal Title: The Journal of biological chemistry Volume: 289 Pages: 29892-911
  • DOI: 10.1074/jbc.M114.580084
  • Peer Reviewed
• [Journal Article] Clock gene Bmal1 is dispensable for intrinsic properties of murine hematopoietic stem cells (2014)
  • Author(s): Ieyasu A, Tajima Y, Shimba S, Nakauchi H, Yamazaki S
  • Journal Title: Journal of negative results in biomedicine Volume: 13 Pages: 4
  • DOI: 10.1186/1477-5751-13-4
  • Peer Reviewed / Open Access
• [Journal Article] Generation of induced pluripotent stem cells derived from primary and secondary myelofibrosis patient samples (2014)
  • Author(s): Hosoi M, Kumano K, Taoka K, Arai S, Kataoka K, Ueda K, Kamikubo Y, Takayama N, Otsu M, Eto K, Nakauchi H, Kurokawa M
  • Journal Title: Experimental hematology Volume: 42 Pages: 816-25
  • DOI: 10.1016/j.exphem.2014.03.010
  • Peer Reviewed
• [Journal Article] A chemical probe that labels human pluripotent stem cells (2014)
  • Author(s): Hirata N, Nakagawa M, Fujibayashi Y, Yamauchi K, Murata A, Minami I, Tomioka M, Kondo T, Kuo TF, Endo H, Inoue H, Sato S, Ando S, Kawazoe Y, Aiba K, Nagata K, Kawase E, Chang YT, Suemori H, Eto K, Nakauchi H, Yamanaka S, Nakatsuji N, Ueda K, Uesugi M
  • Journal Title: Cell reports Volume: 6 Pages: 1165-74
  • DOI: 10.1016/j.celrep.2014.02.006
  • Peer Reviewed / Open Access
• [Journal Article] The generation of induced pluripotent stem cells (iPSCs) from patients with infantile and late-onset types of Pompe disease and the effects of treatment with acid-alpha-glucosidase in Pompe's iPSCs (2014)
  • Author(s): Higuchi T, Kawagoe S, Otsu M, Shimada Y, Kobayashi H, Hirayama R, Eto K, Ida H, Ohashi T, Nakauchi H, Eto Y
  • Journal Title: Molecular genetics and metabolism Volume: 112 Pages: 44-8
  • DOI: 10.1016/j.ymgme.2014.02.012
  • Peer Reviewed
• [Presentation] Myeloid-biased hematopoiesis in aged mouse bone marrow (2015)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Japan-US Hematology conference
  • Place of Presentation: Hawaii, U.S.
  • Year and Date: 2015-03-16 – 2015-03-18
  • Invited
• [Presentation] The Stem Cell Niche (2015)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Gordon Research Conference
  • Place of Presentation: Ventura Beach Marriott, Ventura, CA. US
  • Year and Date: 2015-02-15 – 2015-02-20
  • Invited
• [Presentation] In vivo generation of hematopoietic stem cells from iPSCs (2014)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: JST-CIHR Epigenetics F2F Meeting
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2014-10-29 – 2014-10-29
  • Invited
• [Presentation] Single cell transplantation and clonal analysis of hematopoietic stem cells: Exploring heterogeneity and hierarchy (2014)
  • Author(s): Hiromitsu Nakauchi
  • Organizer: Till&McCulloch Meetings
  • Place of Presentation: Ottawa, Canada
  • Year and Date: 2014-10-29 – 2014-10-29
  • Invited
• [Patent(Industrial Property Rights)] 造血幹細胞を減少させる組成物およびその製造法 (2014)
  • Inventor(s): 中内 啓光、山崎 聡、田矢 祐規
  • Industrial Property Rights Holder: 国立大学法人 東京大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-237874
  • Filing Date: 2014-11-25