Evaluation of human iPSCs by neural differentaition and tumorigenicity

• Project/Area Number: 23689017
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Keio University
• Principal Investigator: OKADA Yohei 慶應義塾大学, 医学部, 訪問准教授 (30383714)
• Project Period (FY): 2011-11-18 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2013: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2012: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: ヒトiPS細胞 / 品質評価 / 神経分化 / 造腫瘍性

Research Abstract

Human-induced pluripotent stem cells (hiPSCs) hold great promise for regenerative medicine. Despite the importance in evaluating their quality for future cell therapy, there are no precise analyses for assessing abnormal differentiation and tumorigenicity. We demonstrated that pre-evaluated hiPSC clones, established by retroviruses or integration-free episomal vectors, may exhibit glioma-like tumor formation by the transplantation of hiPSC-derived neural stem/progenitor cells into NOD/SCID mice. Notably, the tumorigenicities were closely associated with incomplete reprogramming of hiPSCs, revealed by the expressions of newly identified human embryonic stem cell signature genes or DNA repair genes. This incomplete reprogramming resulted in genomic instability not in an undifferentiated state, but during neural differentiation. Moreover, cluster of DNA repair genes may provide a useful "scorecard" for easy and quick evaluation of the incomplete reprogramming of hiPSCs.

Research Products

• [Journal Article] Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes (2014)
  • Author(s): Numasawa-Kuroiwa Y, Okada Y#, Shibata S, Kishi N, Akamatsu W, Shoji M, Nakanishi A, Oyama M, Osaka H, Inoue K, Takahashi K, Yamanaka S, Kosaki K, Takahashi T, Okano H#(#corresponding authors)
  • Journal Title: Stem Cell Report Volume: 2(5) Pages: 648-661
  • Peer Reviewed
• [Journal Article] Increased l1 retrotransposition in the neuroral genome in schizophrenia. (2014)
  • Author(s): Miki Bundo, Manabu Toyoshima, Yohei Okada, Wado Akamatsu, Junko Ueda, Taeko Nemoto-Miyauchi, Fumiko Sunaga, Michihiro Toritsuka, Daisuke Ikawa, Akiyoshi Kakita, Motoichiro Kato, Kiyoto Kasai, Toshifumi Kishimoto, Hiroyuki Nawa, Hideyuki Okano, Takeo Yoshikawa, Tadafumi Katoemail, Kazuya Iwamoto
  • Journal Title: Neuron Volume: 81 Issue: 2 Pages: 306-313
  • DOI: 10.1016/j.neuron.2013.10.053
  • Peer Reviewed
• [Journal Article] Involvement of Endoplasmic Reticulum Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by Induced-Pluripotent-Stem Cell-Derived Oligodendrocytes (2014)
  • Author(s): Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M, Nakanishi A, Oyama M, Osaka H, Inoue K, Takahashi K, Yamanaka S, Kosaki K, Takahashi T, Okano H
  • Journal Title: Stem Cell Report Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Involvement of Endoplasmic Reticulum Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1Missense Mutations Shown by Induced-Pluripotent-Stem Cell-Derived Oligodendrocytes (2014)
  • Author(s): Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M, Nakanishi A, Oyama M, Osaka H, Inoue K, Takahashi K, Yamanaka S, Kosaki K, Takahashi T, Okano H
  • Journal Title: Stem Cell Report Volume: 印刷中
  • Peer Reviewed
• [Journal Article] A human Dravet syndrome model from patient induced pluripotent stem cells. (2013)
  • Author(s): Higurashi N, Uchida T, Lossin C, Misumi Y, Okada Y, Akamatsu W, Imaizumi Y, Zhang B, Nabeshima K, Mori MX, Katsurabayashi S, Shirasaka Y, Okano H, Hirose S.
  • Journal Title: Mol Brain Volume: 6 Issue: 1 Pages: 19-19
  • DOI: 10.1186/1756-6606-6-19
  • Peer Reviewed
• [Journal Article] Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy. (2013)
  • Author(s): Nihei Y, Ito D, Okada Y, Akamatsu W, Yagi T, Yoshizaki T, Okano H, Suzuki N.
  • Journal Title: J Biol Chem. Volume: 288 Issue: 12 Pages: 8043-8052
  • DOI: 10.1074/jbc.m112.408211
  • Peer Reviewed
• [Journal Article] Steps toward safe cell therapy using induced pluripotent stem cells (2013)
  • Author(s): Okano H
  • Journal Title: Circulation Research Volume: 112 Issue: 3 Pages: 523-33
  • DOI: 10.1161/circresaha.111.256149
  • Peer Reviewed
• [Journal Article] Human Decidua-Derived Mesenchymal Cells Are a Promising Source for the Generation and Cell Banking of Human Induced Pluripotent Stem Cells (2013)
  • Author(s): Tomoko Shofuda, Yoshikazu Sugimoto, et al.
  • Journal Title: Cell Medicine Volume: 4 Issue: 3 Pages: 125-147
  • DOI: 10.3727/215517912x658918
  • Peer Reviewed
• [Journal Article] Pre-Evaluated Safe Human iPSC-Derived Neural Stem Cells Promote Functional Recovery after Spinal Cord Injury in Common Marmoset without Tumorigenicity (2012)
  • Author(s): Kobayashi Y, Okada Y
  • Journal Title: PLoS One Volume: 7 Issue: 12 Pages: e52787-e52787
  • DOI: 10.1371/journal.pone.0052787
  • Peer Reviewed
• [Journal Article] Multiple analyses of G-protein coupled receptor (GPCR) expression in the development of gefitinib-resistance in transforming non-small-cell lung cancer. (2012)
  • Author(s): Kuzumaki N
  • Journal Title: PLoS One Volume: 7 Issue: 10 Pages: e44368-e44368
  • DOI: 10.1371/journal.pone.0044368
  • Peer Reviewed
• [Journal Article] Efficient Derivation of Multipotent Neural Stem/Progenitor Cells from Non-human Primate Embryonic Stem Cells (2012)
  • Author(s): Shimada H, Okada Y, Ibata K, Ebise H, Ota S, Tomioka I, Nomura T, Maeda T, Kohda K, Yuzaki M, Sasaki E, Nakamura M, Okano H
  • Journal Title: PLoS One Volume: 7(11) Issue: 11 Pages: e49469-e49469
  • DOI: 10.1371/journal.pone.0049469
  • Peer Reviewed
• [Journal Article] Mitochondrial dysfunction associated with increased oxidative stress and -synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. (2012)
  • Author(s): Imaizumi Y
  • Journal Title: Mol Brain Volume: 5 Issue: 1 Pages: 35-35
  • DOI: 10.1186/1756-6606-5-35
  • Peer Reviewed
• [Journal Article] Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research (2012)
  • Author(s): Yagi, T.
  • Journal Title: PLoS ONE Volume: 7 Issue: 7 Pages: e41572-e41572
  • DOI: 10.1371/journal.pone.0041572
  • Peer Reviewed
• [Journal Article] RNA-Binding Protein Musashi1 Modulates Glioma Cell Growth through the Post-Transcriptional Regulation of Notch and PI(3) Kinase/Akt Signaling Pathways (2012)
  • Author(s): Muto J, Imai T, Ogawa D, Nishimoto Y, Okada Y, Mabuchi Y, Kawase T, Iwanami A, Mischel PS, Saya H, Yoshida K, Matsuzaki Y, Okano H
  • Journal Title: PLoS One Volume: 7(3) Issue: 3 Pages: e33431-e33431
  • DOI: 10.1371/journal.pone.0033431
  • Peer Reviewed
• [Journal Article] Effect of k-opioid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells (2012)
  • Author(s): Kuzumaki N, Suzuki A, Narita M, Hosoya T, Nagasawa A, Imai S, Yamamizu K, Morita H, Nagase H, Okada Y, Okano HJ, Yamashita JK, Okano H, Suzuki T, Narita M
  • Journal Title: Br J Cancer Volume: 106(Epub 2012 Feb 16) Issue: 6 Pages: 1148-1152
  • DOI: 10.1038/bjc.2011.574
  • Peer Reviewed
• [Journal Article] Grafted human-induced pluripotent stem-cell-derived neurospheres promotemotor functional recovery after spinal cord injury in mice (2011)
  • Author(s): Nori, S., et al
  • Journal Title: Proceedings of National Academy of Science U.S.A. Volume: 108 Issue: 40 Pages: 16825-16830
  • DOI: 10.1073/pnas.1108077108
  • Peer Reviewed
• [Journal Article] Modeling familial Alzheimer's disease with induced pluripotent stem cells (2011)
  • Author(s): Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N
  • Journal Title: Human Molecular Genetics Volume: 20 Issue: 23 Pages: 4530-9
  • DOI: 10.1093/hmg/ddr394
  • Peer Reviewed
• [Journal Article] Musashi 1 cooperates in abnormal cell LINeage protein 28 (Lin28)-mediated Let-7 family microRNA biogenesis in early neural differentiation (2011)
  • Author(s): Kawahara, H., Okada, Y., et al
  • Journal Title: J Biol Chem Volume: 286 Issue: 18 Pages: 16121-30
  • DOI: 10.1074/jbc.m110.199166
  • Peer Reviewed
• [Journal Article] Generation of human melanocytes from induced pluripotent stem cells (2011)
  • Author(s): Ohta S, Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, Amagai M, Matsuzaki Y, Yamanaka S, Okano H, Kawakami Y
  • Journal Title: PLoS One Volume: 6(1) Issue: 1 Pages: e16182-e16182
  • DOI: 10.1371/journal.pone.0016182
  • Peer Reviewed
• [Journal Article] Gene targeting and subsequent site-specific transgenesis at theβ-actin(ACTB) locus in common marmoset embryonic stem cells (2011)
  • Author(s): Shiozawa, S., Suemizu, H.(12名・8番目)
  • Journal Title: Stem Cells Dev Volume: 20 Issue: 9 Pages: 1587-99
  • DOI: 10.1089/scd.2010.0351
  • Peer Reviewed
• [Presentation] Invompletely reprogrammed human iPSCs form glioma-like tumors through genomic instability during differentiation (2014)
  • Author(s): Okada Y
  • Organizer: Kyoto University/Keio Universiy/MD Anderson Cancer Center (MDACC) Joint Conference, iPS and Stem Cells in Cancer Research, Kyoto
  • Place of Presentation: Kyoto Japan(シンポジウム)
  • Year and Date: 2014-04-17
  • Invited
• [Presentation] iPS細胞を用いた神経疾患研究 (2014)
  • Author(s): 岡田洋平
  • Organizer: 愛知医科大学加齢医科学研究所30周年記念講演会
  • Place of Presentation: 名古屋(特別講演)
  • Year and Date: 2014-02-21
  • Invited
• [Presentation] iPS細胞を用いた神経疾患研究 (2014)
  • Author(s): 岡田洋平
  • Organizer: 独立行政法人国立病院機構鈴鹿病院創立70周年記念市民講演会
  • Place of Presentation: 鈴鹿(市民講演会)
  • Year and Date: 2014-02-15
  • Invited
• [Presentation] 多能性幹細胞を用いた神経疾患研究 (2014)
  • Author(s): 岡田洋平
  • Organizer: ハンドフロンティア前向き研究会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-02-14
  • Invited
• [Presentation] 多能性幹細胞、神経幹細胞を用いた神経再生 (2014)
  • Author(s): 岡田洋平
  • Organizer: 愛知医科大学糖神合同セミナー
  • Place of Presentation: 名古屋
  • Year and Date: 2014-02-04
  • Invited
• [Presentation] 培養皿の上で神経を作る―多能性幹細胞(ES細胞・iPS細胞)を用いた神経発生,神経再生,病態解析研究 (2013)
  • Author(s): 岡田洋平
  • Organizer: 愛知医科大学先端医学研究センター第13回研究セミナー
  • Place of Presentation: 名古屋
  • Year and Date: 2013-11-11
  • Invited
• [Presentation] iPS細胞を用いた神経再生と病態解析スモンに関する調査研究班 (2013)
  • Author(s): 岡田洋平
  • Organizer: 平成25年度ワークショップ
  • Place of Presentation: 名古屋(特別講演)
  • Year and Date: 2013-07-26
  • Invited
• [Presentation] 多能性幹細胞(ES細胞/iPS細胞)の神経分化誘導とその応用 (2013)
  • Author(s): 岡田洋平
  • Organizer: 第35回神経組織培養研究会
  • Place of Presentation: 大阪(シンポジウム)
  • Year and Date: 2013-06-29
  • Invited
• [Presentation] Incompletely reprogrammed human iPSCs form glioma-like tumors through genomic instability during neural differentiation (2013)
  • Author(s): Okada Y, Miya, F, Koike M, Tomisato S, Tokura T, Ishihara Y, Shimojo D, Hattori C, Kanematsu D, Kanemura Y, Kohda K, Sobue G, Yamanaka S, Yuzaki M, Uchiyama Y, Ikeda E, Tsunoda T, Okano H
  • Organizer: The 11th Stem Cell Research Symposium
  • Place of Presentation: Tokyo Japan(シンポジウム)
  • Year and Date: 2013-05-17
• [Presentation] iPS細胞を用いた神経再生と病態解析 (2013)
  • Author(s): 岡田洋平
  • Organizer: 第4回岐阜脳神経研究会
  • Place of Presentation: 岐阜(特別講演)
  • Year and Date: 2013-02-02
  • Invited
• [Presentation] ヒトiPS細胞由来神経幹細胞の応用とその問題点 (2012)
  • Author(s): 岡田洋平、岡野栄之
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島(シンポジウム)
  • Year and Date: 2012-11-19
  • Invited
• [Presentation] 多能性幹細胞・神経幹細胞を用いた神経再生と病態解析 (2012)
  • Author(s): 岡田洋平
  • Organizer: 第13回埼玉パーキンソン病治療研究会
  • Place of Presentation: 大宮(特別講演)
  • Year and Date: 2012-11-01
  • Invited
• [Presentation] iPS細胞・神経幹細胞で神経系を再生する、兵庫県保険医協会 (2011)
  • Author(s): 岡田洋平
  • Organizer: 第79回総会特別講演
  • Place of Presentation: 神戸(特別講演)
  • Year and Date: 2011-06-19
  • Invited
• [Presentation] 神経分化と造腫瘍性から迫るヒトiPS細胞の品質評価 (2011)
  • Author(s): 岡田洋平、岡野栄之
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋(シンポジウム)
  • Year and Date: 2011-05-20
  • Invited
• [Presentation] 分化能と造腫瘍性から迫るヒトiPS細胞の品質評価 (2011)
  • Author(s): 岡田洋平、岡野栄之
  • Organizer: 第10回日本再生医療学会総会
  • Place of Presentation: 東京(シンポジウム)
  • Year and Date: 2011-03-01
  • Invited
• [Presentation] Incompletely reprogrammed human iPSCs form glioma-like tumors through genomic instability during neural differentiation
  • Author(s): Okada Y, Miya, F, Koike M, Tomisato S, Tokura T, Ishihara Y, Shimojo D, Hattori C, Kanematsu D, Kanemura Y, Kohda K, Sobue G, Yamanaka S, Yuzaki M, Uchiyama Y, Ikeda E, Tsunoda T, Okano H
  • Organizer: The 11th Stem Cell Research Symposium
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] 不完全にリプログラミングされたヒトiPS細胞は分化誘導に伴うゲノム不安定化を通してグリオーマ様腫瘍を形成する
  • Author(s): 岡田洋平、宮冬樹、小池正人、冨里周太、戸倉智子、石原康晴、下門大祐、服部千夏、兼松大介、金村米博、幸田和久、祖父江元、山中伸弥、柚崎通介、内山安男、池田栄二、角田達彦、岡野栄之
  • Organizer: 第36回日本神経科学大会、第56回日本神経化学会大会、第23回日本神経回路学会大会
  • Place of Presentation: 京都
• [Presentation] 多能性幹細胞(ES細胞/iPS細胞)の神経分化誘導とその応用
  • Author(s): 岡田洋平
  • Organizer: 第35回神経組織培養研究会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 培養皿の上で神経を作る―多能性幹細胞（ES細胞・iPS細胞）を用いた神経発生、神経再生、病態解析研究
  • Author(s): 岡田洋平
  • Organizer: 愛知医科大学先端医学研究センター 第13回研究セミナー
  • Place of Presentation: 愛知
  • Invited
• [Presentation] 多能性幹細胞を用いた神経疾患研究
  • Author(s): 岡田洋平
  • Organizer: ハンドフロンティア 第89回 前向き研究会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] iPS細胞を用いた神経疾患研究
  • Author(s): 岡田洋平
  • Organizer: 愛知医科大学加齢医科学研究所30周年記念講演会
  • Place of Presentation: 愛知
  • Invited
• [Presentation] Evaluation of human iPS cells by neural differentiation and tumorigenicity.
  • Author(s): Okada Y, Miya F, Tomisato S, Kanemura Y, Koike M, Kohda K, Yuzaki M, Uchiyama Y, Tsunoda T, Yamanaka S, Okano H
  • Organizer: ISSCR 10th annual Meeting
  • Place of Presentation: Yokohama
• [Presentation] ヒトiPS細胞由来神経幹細胞の応用とその問題点
  • Author(s): 岡田洋平、岡野栄之
  • Organizer: 第24回日本脳循環代謝学会総会
  • Place of Presentation: 広島
  • Invited
• [Presentation] 不完全にリプログラミングされたヒトiPS細胞由来神経幹細胞は分化誘導に伴うゲノム不安定化によりグリオーマ様腫瘍を形成する
  • Author(s): 岡田洋平、宮冬樹、小池正人、冨里周太、兼松大介、金村米博、幸田和久、柚崎通介、内山安男、池田栄二、角田達彦、山中伸弥、岡野栄之
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 多能性幹細胞・神経幹細胞を用いた神経再生と病態解析
  • Author(s): 岡田洋平
  • Organizer: 第13回埼玉パーキンソン病治療研究会
  • Place of Presentation: 大宮
  • Invited
• [Presentation] iPS細胞を用いた神経再生と病態解析
  • Author(s): 岡田洋平
  • Organizer: 第4回岐阜脳神経研究会
  • Place of Presentation: 岐阜
  • Invited
• [Presentation] 神経分化と造腫瘍性から迫るヒトiPS細胞の品質評価
  • Author(s): 岡田洋平
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] Evaluation of human iPS cells by neural differentiation and tumorigenicity.
  • Author(s): Okada Y
  • Organizer: IBRO World congress of Neuroscience
  • Place of Presentation: フィレンツェ（イタリア）
• [Presentation] 神経分化と造腫瘍性から迫るヒトiPS細胞の品質評価
  • Author(s): 岡田洋平
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: 横浜
• [Book] 実践編[2]9.神経幹細胞への分化誘導、実験医学別冊「ES・iPS細胞実験スタンダード」 (2014)
  • Author(s): 岡田洋平、岡野栄之
  • Total Pages: 355
  • Publisher: 羊土社
• [Book] 実験医学別冊「ES・iPS細胞実験スタンダード」 (2014)
  • Author(s): 岡田洋平、岡野栄之
  • Total Pages: 355
  • Publisher: 羊土社
• [Book] ヒトiPS細胞由来神経幹細胞の応用とその問題点、脳循環代謝24 (2013)
  • Author(s): 岡田洋平
  • Publisher: メディカルトリビューン
• [Book] iPS細胞を用いた脊髄損傷治療、Brain Nerve 64 (1) (2012)
  • Author(s): 海苔聡、辻収彦、岡田洋平、戸山芳昭、岡野栄之、中村雅也
  • Publisher: 医学書院
• [Book] 神経分化と造腫瘍性から迫るヒトiPS細胞の品質評価臨床神経学51(11) (2011)
  • Author(s): 岡田洋平、岡野栄之
  • Publisher: 日本神経学会
• [Remarks]
  • URL: http://www.careerpath-prj.keio.ac.jp/kanrinmaru/scholar/okada/
• [Patent(Industrial Property Rights)] iPS細胞のクローンの選択方法、及び その選択方法に用いる遺伝子の選択方法 (2012)
  • Inventor(s): 岡田洋平、岡野栄之、角田達彦、宮 冬樹
  • Industrial Property Rights Holder: 学校法人慶應義塾
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-02-27
  • Overseas