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研究者紹介

講師 田久保 圭誉
(Keiyo Takubo, Assistant Professor)

講師 田久保 圭誉

講師
田久保 圭誉

■研究テーマ
幹細胞代謝の統合的解析と操作
■Keywords
造血幹細胞、低酸素ニッチ、メタボロミクス

プロフィール

学歴
平成15年3月 慶應義塾大学医学部医学科卒業
平成19年3月 慶應義塾大学大学院医学研究科生理系発生分化生物学専攻修了 博士(医学)取得


研究歴
平成15年4月より 慶應義塾大学医学部発生・分化生物学の須田年生教授の指導の下に哺乳類成体幹細胞システムの恒常性維持機構に関する研究に従事


職歴
日本学術振興会特別研究員、慶應義塾大学医学部発生・分化生物学講座 助教を経て


平成23年12月より
慶應義塾大学医学部発生・分化生物学講座 専任講師


平成25年2月より
慶應義塾大学医学部坂口講座テニュアトラック・プログラム専任講師


代表的論文
1) Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T, Hirao A, Suematsu M, Suda T Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells.
Cell Stem Cell 12:49-61, 2013 (KT is a corresponding author of this paper.)


2) Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.
Cell Stem Cell 7:391-402, 2010 (KT is a corresponding author of this paper.)


3) Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada W, Arai F, Hirao A, Suda T. Stem Cell Defects in ATM-deficient Undifferentiated Spermatogonia through DNA Damage-induced Cell Cycle Arrest.
Cell Stem Cell 2:170-82, 2008 (KT is a corresponding author of this paper.)


主な受賞
平成20年10月 日本血液学会奨励賞(日本血液学会)
平成25年9月 日本生化学会奨励賞(日本生化学会)
平成26年1月 慶應医学賞医学研究奨励賞(慶應義塾大学)
平成26年4月 文部科学大臣若手科学者賞(文部科学省)

研究内容

体性幹細胞はニッチと呼ばれる微小環境によって維持されて自己複製能と多分化能を維持する。病態や老化によってニッチに異常が起こり、幹細胞システムが障害されると考えられているがそのメカニズムは不明である。本プログラムでは複数のニッチ細胞とニッチ因子によって重層的に制御されている造血幹細胞ニッチをモデルとした解析を進める。これまでに哺乳類の造血幹細胞は成体では主に骨髄の低酸素ニッチに存在し、細胞内低酸素状態を保ちつつ低酸素応答システムであるVHL/HIF-1制御系を介して細胞周期を静止期に止めて代謝恒常性を保っていることを見出してきており(Cell Stem Cell 2010, 2013)、本プログラムではより統合的・網羅的なアプローチから造血幹細胞ニッチの代謝プログラムを理解することを目指す。得られた知見からストレス造血や病態に伴う幹細胞ニッチの障害を回避する戦略の開発や、体外で幹細胞を維持する技術の開発を目指す。

論文業績

・英文原著論文(査読有)

(1)    Kunimoto H, Fukuchi Y, Sakurai M, Takubo K, Okamoto S, Nakajima H. Tet2-mutated myeloid progenitors possess aberrant in vitro self-renewal capacity.

Blood. 2014 May 1;123(18):2897-9.

(2)    Kinoshita T, Nagamatsu G, Saito S, Takubo K, Horimoto K, Suda T. Telomerase Reverse Transcriptase Has an Extratelomeric Function in Somatic Cell Reprogramming.

J Biol Chem. 2014 May 30;289(22):15776-15787.

(3)    Kawasaki K, Oommen S, Otsuka-Tanaka Y, Hishinuma M, Nomoto T, Maeda T, Takubo K, Suda T, Sharpe PT, Ohazama A. R-spondins/Lgrs expression in tooth development. Kawasaki M, Porntaveetus T,

Dev Dyn. 2014 Jun;243(6):844-51.

(4)    #Kobayashi CI, #*Takubo K (#equal contribution), Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T. The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells. Blood. 2014 Apr 17;123(16):2540-9.

[*K. Takubo is a corresponding author of this paper.]

(5)    Nagamachi A, Nakata Y, Ueda T, Yamasaki N, Ebihara Y, Tsuji K, Honda Z, Takubo K, Suda T, Oda H, Inaba T, Honda H. Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.

PLoS One. 2014 Jan 31;9(1):e87425.

(6)    Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, Takubo K, Suda T, Nakamura T, Wolff L, Honda H, Inaba T. Haploinsufficiency of SAMD9L, an Endosome Fusion Facilitator, Causes Myeloid Malignancies in Mice Mimicking Human Diseases with Monosomy 7.

Cancer Cell. 2013 Sep 9;24(3):305-317.

(7)    Mulvaney JF, Yatteau A, Sun WW, Jacques B, Takubo K, Suda T, Yamada W, Dabdoub A. Secreted factor R-Spondin 2 is involved in refinement of patterning of the mammalian cochlea.

Dev Dyn. 2013 Feb;242(2):179-188.

(8)    *Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T, Hirao A, Suematsu M, Suda T. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells.

Cell Stem Cell. 2013 Jan 3;12(1):49-61.

[*K. Takubo is a corresponding author of this paper.]

(9)    Ikushima YM, Arai F, Hosokawa K, Toyama H, Takubo K, Furuyashiki T, Narumiya S, Suda T. Prostaglandin E(2) regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells.

Blood. 2013 Mar 14;121(11):1995-2007.

(10)  Nagamatsu G, Kosaka T, Saito S, Honda H, Takubo K, Kinoshita T, Akiyama H, Sudo T, Horimoto K, Oya M, Suda T. Induction of pluripotent stem cells from primordial germ cells by single reprogramming factors.

Stem Cells. 2013 Mar;31(3):479-487.

(11)  Takaesu G, Inagaki M, Takubo K, Mishina Y, Hess PR, Dean GA, Yoshimura A, Matsumoto K, Suda T, Ninomiya-Tsuji J. TAK1 (MAP3K7) signaling regulates hematopoietic stem cells through TNF-dependent and -independent mechanisms.

PLoS One. 2012;7(11):e51073.

(12)  Nagamatsu G, Saito S, Kosaka T, Takubo K, Kinoshita T, Oya M, Horimoto K, Suda T. Optimal ratio of transcription factors for somatic cell reprogramming.

J Biol Chem. 2012 Oct 19;287(43):36273-36282.

(13)  Nagamatsu G, Kosaka T, Saito S, Takubo K, Akiyama H, Sudo T, Horimoto K, Oya M, Suda T. Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice.

Biol Reprod. 2012 Jun 14;86(6):182.

(14)  #Iriuchishima H, #*Takubo K (#equal contribution), Miyakawa Y, Nakamura-Ishizu A, Miyauchi Y, Fujita N, Miyamoto K, Miyamoto T, Ikeda E, Kizaki M, Nojima Y, Suda T. Neovascular niche for human myeloma cells in immunodeficient mouse bone.

PLoS One. 2012;7(2):e30557.

[*K. Takubo is a corresponding author of this paper.]

(15)  Ikejiri A, Nagai S, Goda N, Kurebayashi Y, Osada-Oka M, Takubo K, Suda T, Koyasu S.  Dynamic regulation of Th17 differentiation by oxygen concentrations.

Int Immunol. 2012 Mar;24(3):137-146.

(16)  Kubota Y, Takubo K, Hirashima M, Nagoshi N, Kishi K, Okuno Y, Nakamura-Ishizu A, Sano K, Murakami M, Ema M, Omatsu Y, Takahashi S, Nagasawa T, Shibuya M, Okano H, Suda T. Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero.

J Exp Med. 2011 May 9;208(5):949-960

(17)  Kinoshita T, Nagamatsu G, Kosaka T, Takubo K, Hotta A, Ellis J, Suda T. Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells.

Biochem Biophys Res Commun. 2011 Apr 8;407(2):321-326.

(18)  #Iriuchishima H, #Takubo K (#equal contribution), Matsuoka S, Onoyama I, Nakayama KI,  Nojima Y, Suda T. Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7alpha overexpression.

Blood. 2011 Feb 24;117(8):2373-2377

[*K. Takubo is a corresponding author of this paper.]

(19)  Nitta E, Yamashita M, Hosokawa K, Xian M, Takubo K, Arai F, Nakada S, Suda T. Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism.

Blood. 2011 Apr 21;117(16):4169-4180.

(20)  Nagamatsu G, Kosaka T, Kawasumi M, Kinoshita T, Takubo K, Akiyama H, Sudo T, Kobayashi T, Oya M, Suda T. A germ cell-specific gene, Prmt5, works in somatic cell reprogramming.

J Biol Chem. 2011 Mar 25;286(12):10641-10648.

(21)  #Honda H, #Takubo K (#equal contribution), Oda H, Kosaki K, Tazaki T, Yamasaki N, Miyazaki K, Moore KA, Honda Z, Suda T, Lemischka IR. Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation.

Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2468-2473

(22)  *Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T. Regulation of the HIF-1a Level is Essential for Hematopoietic Stem Cells.

Cell Stem Cell. 2010 Sep 3;7(3):391-402.

[*K. Takubo is a corresponding author of this paper.]

(23)  Shima H, *Takubo K, Tago N, Iwasaki H, Arai F, Takahashi T, Suda T. Acquisition of G(0) state by CD34-positive cord blood cells after bone marrow transplantation.

Exp Hematol. 2010 Dec;38(12):1231-1240.

[*K. Takubo is a corresponding author of this paper.]

(24)  Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon MC, Johnson RS, Suematsu M, Tsubota K, Ishida S, Goda N, Suda T, Okano H. von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina.

Development. 2010 May;137(9):1563-1571.

(25)  Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Hembree M, Yin T, Nakamura Y, Gomei Y, Takubo K, Shiama H, Matsuoka S, Li L, Suda T. Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow.

Cell Stem Cell. 2010 Mar 5;6(3):194-198.

(26)  Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis.

J Exp Med. 2009 May 11;206(5):1089-1102.

(27)  Yamada W, Nagao K, Horikoshi K, Fujikura A, Ikeda E, Inagaki Y, Kakitani M, Tomizuka K, Miyazaki H, Suda T, *Takubo K. Craniofacial malformation in R-spondin2 knockout mice.

Biochem Biophys Res Commun. 2009 Apr 10;381(3):453-458.

[*K. Takubo is a corresponding author of this paper.]

(28)  Shima H, Takubo K, Iwasaki H, Yoshihara H, Gomei Y, Hosokawa K, Arai F, Takahashi T, Suda T. Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice.

Biochem Biophys Res Commun. 2009 Jan 16;378(3):467-472.

(29)  Ohmura M, Naka K, Hoshii T, Muraguchi T, Shugo H, Tamase A, Uema N, Ooshio T, Arai F, Takubo K, Nagamatsu G, Hamaguchi I, Takagi M, Ishihara M, Sakurada K, Miyaji H, Suda T, Hirao A. Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity.

Stem Cells. 2008 Dec;26(12):3237-46.

(30)  Ikeda E, Takubo K, Kodama T, Okada Y. Brain-specific expression of vascular endothelial growth factor 146 correlates with the blood-brain barrier induction in quail embryos.

Dev Neurosci. 2008;30(5):331-9.

(31)  *Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada W, Arai F, Hirao A, Suda T. Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell-cycle arrest.

Cell Stem Cell. 2008 Feb 7;2(2):170-82.

[*K. Takubo is a corresponding author of this paper.]

(32)  Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyamoto K, Miyazaki H, Takahashi T, Suda T. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche.

Cell Stem Cell. 2007 Dec 13;1(6):685-97.

(33)  Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K, Nakayama KI, Harada M, Motoyama N, Suda T, Hirao A. Foxo3a is essential for maintenance of the hematopoietic stem cell pool.

Cell Stem Cell. 2007 Jun 7;1(1):101-12.

(34)  Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K, Mashimo Y, Oguro H, Nitta E, Ito K, Miyamoto K, Yoshiwara H, Hosokawa K, Nakamura Y, Gomei Y, Iwasaki H, Hayashi Y, Matsuzaki Y, Nakayama K, Ikeda Y, Hata A, Chiba S, Nakayama KI, Suda T. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL.

Genes Dev. 2008 Apr 15;22(8):986-91.

(35)  #Kubota Y, #Takubo K (#equal contribution), Suda T. Bone marrow long label-retaining cells reside in the sinusoidal hypoxic niche.

Biochem Biophys Res Commun. 2008 Feb 8;366(2):335-9.

(36)  Morita K, Miyamoto T, Fujita N, Kubota Y, Ito K, Takubo K, Miyamoto K, Ninomiya K, Suzuki T, Iwasaki R, Yagi M, Takaishi H, Toyama Y, Suda T. Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification.

J Exp Med. 2007 Jul 9;204(7):1613-23.

(37)  Koto T, Takubo K, Ishida S, Shinoda H, Inoue M, Tsubota K, Okada Y, Ikeda E. Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells.

Am J Pathol. 2007 Apr;170(4):1389-97.

(38)  Ito K, Takubo K, Arai F, Satoh H, Matsuoka S, Ohmura M, Naka K, Azuma M, Miyamoto K, Hosokawa K, Ikeda Y, Mak TW, Suda T, Hirao A. Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes.

J Immunol. 2007 Jan 1;178(1):103-10.

(39)  *Takubo K, Hirao A, Ohmura M, Azuma M, Arai F, Nagamatsu G, Suda T. Premeiotic germ cell defect in seminiferous tubules of Atm-null testis.

Biochem Biophys Res Commun. 2006 Dec 29;351(4):993-8.

[*K. Takubo is a corresponding author of this paper.]

(40)  Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.

Nat Med. 2006 Apr;12(4):446-51.

(41)  Azuma M, Hirao A, Takubo K, Hamaguchi I, Kitamura T, Suda T. A quantitative matrigel assay for assessing repopulating capacity of prostate stem cells.

Biochem Biophys Res Commun. 2005 Dec 16;338(2):1164-70.

(42)  Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N, Ikeda Y, Mak TW, Suda T. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells.

Nature. 2004 Oct 21;431(7011):997-1002.

(43)  Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.

Cell. 2004 Jul 23;118(2):149-61.

 

・英文総説論文,解説記事

(44)  Takubo K, Suda T. Opening the door for HIF1α tuning.

Blood. 2014 Jan 9;123(2):151-2. (査読無)

(45)  *Takubo K, Suda T. Roles of the hypoxia response system in hematopoietic and leukemic stem cells.

Int J Hematol. 2012 May;95(5):478-483 (査読有)

[*K. Takubo is a corresponding author of this paper.]

(46)  Suda T, Takubo K, Semenza G. Metabolic regulation of hematopoietic stem cells in the hypoxic niche.

Cell Stem Cell. 2011 Oct;9(4):298-310. (査読有)

 

・著書・日本語総説(査読有)

(47)  *Takubo K. The Hypoxia Regulatory System in Hematopoietic Stem Cells.

Advances in Hematopoietic Stem Cell Research, book edited by Rosana Pelayo, ISBN 978-953-307-930-1, Published: January 27, 2012

[*K. Takubo is a corresponding author of this chapter.]

(48)  *田久保圭誉、代謝プログラムによる幹細胞の機能の制御

領域融合レビュー 20131111 (http://leading.lifesciencedb.jp/2-e012/)

[*K. Takubo is a corresponding author of this paper.]

(49)  *田久保圭誉、須田年生 HIF-1a量の精密な調節は造血幹細胞の維持に重要である

新着論文レビューFirst Author's 2010930(http://first.lifesciencedb.jp/archives/955)

[*K. Takubo is a corresponding author of this paper.] 

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