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Study on the inductive efficiency and stability of iPS cells derived from human dental pulp cells

Research Project

Project/Area Number 26293426
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Surgical dentistry
Research InstitutionGifu University

Principal Investigator

SHIBATA TOSHIYUKI  岐阜大学, 大学院医学系研究科, 教授 (50226172)

Co-Investigator(Kenkyū-buntansha) 石崎 明  岩手医科大学, 歯学部, 教授 (20356439)
川口 知子 (武田知子 / 川口 知子(武田知子))  岐阜大学, 医学部附属病院, 医員 (30509815)
飯田 一規  岐阜大学, 大学院医学系研究科, 助教 (30585237)
畠山 大二郎  岐阜大学, 医学部附属病院, 講師 (60377653)
玉置 也剛  岐阜大学, 医学(系)研究科(研究院), 助教 (40585303)
Project Period (FY) 2014-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000)
Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2016: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2015: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywords再生医学 / 歯髄 / iPS細胞 / ヒト歯髄細胞 / 良質化 / ヒト歯髄
Outline of Final Research Achievements

In this study, we examined the inductive efficiency and stability of iPS cells derived from human dental pulp cells. Our results were as follows; 1. Hypoxia condition improved the cell growth and establishing efficiency of primary culture. Furthermore, hypoxia condition was effective and useful for the stemness and high differential potency and could improve the efficiency of iPS cell induction and its quality. 2. Difference of DLX4 expression was observed between high and low inductive cell line to iPS cells. 3. DLX4 improved the inductive efficiency and quality of iPS cell colonies. Only DLX4 and Oct/Sox highly induced iPS cells as well as Oct/Sox, Klf4 and c-Myc. These findings suggested that DLX4 might play a replaceable role of Klf4 and c-Myc. 4. To reveal the DLX4 function engaging to TGFb signal pathway, we examined the induction under TGFb stimulation.TGFb stimulation significantly reduced the inductive efficiency and without the alternation of smad signal pathway.

Academic Significance and Societal Importance of the Research Achievements

iPS細胞の臨床応用において,遺伝子導入操作のや不均一性による「良いiPS細胞」とがん化にも繋がる「悪いiPS細胞」が大きな課題となっており「良質なiPS細胞を効率良く生み出す方策」が強く求められている。本研究では,iPS細胞の良質化・効率化を向上させる新たな因子DLX4を見出し,その機能解析を試みた。結果,DLX4が従来のKlf4, c-Mycに代替し良質なiPS細胞コロニーをもたらすこと,DLX4がTGFβシグナルに応答することより遺伝子操作に依らない細胞の外部刺激により細胞初期化を促進する可能性を見出した。また,研究に用いた歯髄幹細胞が再生医療資源として有用であることを示した。

Report

(6 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (28 results)

All 2018 2017 2016 2015 2014

All Journal Article (17 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 17 results,  Open Access: 17 results,  Acknowledgement Compliant: 7 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] FGF2-Responsive Genes in human Dental Pulp Cells Assessed using a Rat Spinal Cord Injury Model2018

    • Author(s)
      Ken Sugiyama, Kosuke Nagashima, Takahiro Miwa, Yuta Shimizu, Tomoko Kawaguchi, Kazuki Iida, Naritaka Tamaoki, Daijiro Hatakeyama, Hitomi Aoki, Chikara Abe, Hironobu Morita, Takahiro Kunisada, Toshiyuki Shibata, Hidefumi Fukumitsu, and Ken-ichi Tezuka
    • Journal Title

      Journal of Bone and Mineral Metabolism.

      Volume: 印刷中 Issue: 3 Pages: 467-474

    • DOI

      10.1007/s00774-018-0954-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IL-1β and TNF-α suppress TGF-β-promoted NGF expression in periodontal ligament-derived fibroblasts through inactivation of TGF-β-induced Smad2/3-, and p38 MAPK-mediated signals2018

    • Author(s)
      Ohta M., Chosa N., Kyakumoto S., Yokota S., Okubo N., Nemoto A., Kamo M., Joh S., Satoh K., Ishisaki A.
    • Journal Title

      International Journal of Molecular Medicine

      Volume: 43 Pages: 1484-1494

    • DOI

      10.3892/ijmm.2018.3714

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two novel mechanisms for maintenance of stemness in mesenchymal stem cells: SCRG1/BST1 axis and cell?cell adhesion through N-cadherin2018

    • Author(s)
      Chosa Naoyuki、Ishisaki Akira
    • Journal Title

      Japanese Dental Science Review

      Volume: 54 Issue: 1 Pages: 37-44

    • DOI

      10.1016/j.jdsr.2017.10.001

    • NAID

      50013109048

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell?cell interactions between monocytes/macrophages and synoviocyte-like cells promote inflammatory cell infiltration mediated by augmentation of MCP-1 production in temporomandibular joint2018

    • Author(s)
      Ibi Miho、Horie Sawa、Kyakumoto Seiko、Chosa Naoyuki、Yoshida Mariko、Kamo Masaharu、Ohtsuka Masato、Ishisaki Akira
    • Journal Title

      Bioscience Reports

      Volume: 38 Issue: 2 Pages: 20171217-20171217

    • DOI

      10.1042/bsr20171217

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TMEM207 hinders the tumour suppressor function of WWOX in oral squamous cell carcinoma2018

    • Author(s)
      Bunai Katsuaki、Okubo Hiroshi、Hano Kimika、Inoue Keisuke、Kito Yusuke、Saigo Chiemi、Shibata Toshiyuki、Takeuchi Tamotsu
    • Journal Title

      J Cell Mol Med.

      Volume: 22 Issue: 2 Pages: 1026-1033

    • DOI

      10.1111/jcmm.13456

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Water-soluble factors eluated from surface pre-reacted glass-ionomer filler promote osteoblastic differentiation of human mesenchymal stem cells2017

    • Author(s)
      Nemoto Akira、Chosa Naoyuki、Kyakumoto Seiko、Yokota Seiji、Kamo Masaharu、Noda Mamoru、Ishisaki Akira
    • Journal Title

      Molecular Medicine Reports

      Volume: 17 Pages: 3448-3454

    • DOI

      10.3892/mmr.2017.8287

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transforming growth factor-β1 suppresses bone morphogenetic protein-2-induced mesenchymal-epithelial transition in HSC-4 human oral squamous cell carcinoma cells via Smad1/5/9 pathway suppression.2017

    • Author(s)
      Chiba, T., Ishisaki, A., Kyakumoto, S., Shibata, T., Yamada, H., and Kamo, M.
    • Journal Title

      Oncol. Rep.

      Volume: 37 Issue: 2 Pages: 713-720

    • DOI

      10.3892/or.2016.5338

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Priming with FGF2 stimulates human dental pulp cells to promote axonal regeneration and locomotor function recovery after spinal cord injury2017

    • Author(s)
      Nagashima Kosuke、Miwa Takahiro、Soumiya Hitomi、Ushiro Daisuke、Takeda-Kawaguchi Tomoko、Tamaoki Naritaka、Ishiguro Saho、Sato Yumi、Miyamoto Kei、Ohno Takatoshi、Osawa Masatake、Kunisada Takahiro、Shibata Toshiyuki、Tezuka Ken-ichi、Furukawa Shoei、Fukumitsu Hidefumi
    • Journal Title

      Sci Rep

      Volume: 7 Issue: 1 Pages: 13500-13500

    • DOI

      10.1038/s41598-017-13373-5

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Promotion of cell proliferation by the proto-oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization2017

    • Author(s)
      Nakashima, T. Tomita, H. Hirata, A. Ishida, K. Hisamatsu, K. Hatano, Y. Kanayama, T. Niwa, A. Noguchi, K. Kato, K. Miyazaki, T. Tanaka, T. Shibata, T. Hara, A.
    • Journal Title

      Cancer Med

      Volume: 6 Issue: 10 Pages: 2424-2439

    • DOI

      10.1002/cam4.1157

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhancement of anti-inflammatory and osteogenic abilities of mesenchymal stem cells via cell-to-cell adhesion to periodontal ligament-derived fibroblasts.2017

    • Author(s)
      Suzuki, K., Chosa, N., Sawada, S., Takizawa, N., Yaegashi, T., and Ishisaki, A.
    • Journal Title

      Stem Cells Int.

      Volume: 2017:3296498 Pages: 3296498-3296498

    • DOI

      10.1155/2017/3296498

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.2016

    • Author(s)
      Komatsu Y, Ibi M, Chosa N, Kyakumoto S, Kamo M, Shibata T, Sugiyama Y, Ishisaki A.
    • Journal Title

      Int J Mol Med.

      Volume: 38 Issue: 1 Pages: 139-147

    • DOI

      10.3892/ijmm.2016.2582

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Transforming growth factor-β1 induces invasion ability of HSC-4 human oral squamous cell carcinoma cells through the Slug/Wnt-5b/MMP-10 signalling axis.2016

    • Author(s)
      Hino M, Kamo M, Saito D, Kyakumoto S, Shibata T, Mizuki H, Ishisaki A.
    • Journal Title

      Journal of Biochemistry

      Volume: March 2 Issue: 6 Pages: 1-10

    • DOI

      10.1093/jb/mvw007

    • NAID

      40020869454

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes.2016

    • Author(s)
      Igarashi Y, Chosa N, Sawada S, Kondo H, Yaegashi T, Ishisaki A.
    • Journal Title

      Int J Mol Med.

      Volume: 37(4) Issue: 4 Pages: 1005-1013

    • DOI

      10.3892/ijmm.2016.2502

    • NAID

      120006334508

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Establishment of mesenchymal stem cell lines derived from the bone marrow of GFP-transgenic mice exhibiting diversity in intracellular TGF-β and BMP signaling.2016

    • Author(s)
      Sawada, S., Chosa, N., Takizawa, N., Yokota, J., Igarashi, Y., Tomoda, K., Kondo, H., Yaegashi, T., and Ishisaki, A.
    • Journal Title

      Mol. Med. Rep.

      Volume: 13 Issue: 3 Pages: 2023-2031

    • DOI

      10.3892/mmr.2016.4794

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Conditioned medium of dental pulp cells stimulated by Chinese propolis show neuroprotection and neurite extension in vitro2015

    • Author(s)
      Kudo D, Inden M, Sekine S, Tamaoki N, Iida K, Naito E, Watanabe K, Kamishina H, Shibata T, Hozumi I.
    • Journal Title

      Neurosci Lett

      Volume: 589 Pages: 92-97

    • DOI

      10.1016/j.neulet.2015.01.035

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The homeobox gene DLX4 promotes generation of human induced pluripotent stem cells2014

    • Author(s)
      Naritaka Tamaoki, Kazutoshi Takahashi, Hitomi Aoki, Kazuki Iida, Tomoko Kawaguchi, Daijirou Hatakeyama, Masatoshi Inden, Naoyuki Chosa, Akira Ishisaki, Takahiro Kunisada, Toshiyuki Shibata, Naoki Goshima, Shinya Yamanaka, and Ken-ichi Tezuka
    • Journal Title

      Scientific Reports

      Volume: なし Issue: 1 Pages: 7283-7283

    • DOI

      10.1038/srep07283

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Derivation of iPSCs after culture of human dental pulp cells under defined conditions2014

    • Author(s)
      Takeda-Kawaguchi T, Sugiyama K, Chikusa S, Iida K, Aoki H, Tamaoki N, Hatakeyama D, Kunisada T, Shibata T, Fusaki N, Tezuka K.
    • Journal Title

      PLoS One. 2014 Dec 18;9(12):e115392

      Volume: 18 Issue: 12 Pages: 1-15

    • DOI

      10.1371/journal.pone.0115392

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] HLAハプロタイプホモiPS細胞からのエクソソーム精製2018

    • Author(s)
      清水雄太, 川口知子, 小足周平, 柴田敏之, 國貞隆弘, 手塚建一
    • Organizer
      第72回 NPO法人日本口腔科学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] HLA genome editing in human dental pulp stem cell using ZFN2018

    • Author(s)
      小足周平,青木仁美,川口知子,清水雄太,柴田敏之,國定隆弘,渋谷俊昭,手塚健一
    • Organizer
      104回アメリカ歯周病学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HLA allele selective genome editing in human iPS cells using ZFN2018

    • Author(s)
      小足周平,青木仁美,川口知子,清水雄太,柴田敏之,國定隆弘,渋谷俊昭,手塚健一
    • Organizer
      第66回国際歯科研究会日本部会(JDR)学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒト歯髄細胞におけるHLAアリル選択的なゲノムエッディティング2018

    • Author(s)
      小足周平,青木仁美,川口知子,清水雄太,柴田敏之,国貞隆弘,手塚健一
    • Organizer
      第17回日本再生医療学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ヒト歯髄細胞における脊髄損傷後の回復効果と相関するFGF2応答性遺伝子の検索2018

    • Author(s)
      杉山健、飯田一規、川口知子、畠山大二郎、柴田敏之,国貞隆弘,手塚健一
    • Organizer
      第17回日本再生医療学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ヒト歯髄細胞の再生医療への活用2017

    • Author(s)
      柴田 敏之
    • Organizer
      第16回日本再生医療学会総会
    • Place of Presentation
      仙台国際センター(仙台市)
    • Year and Date
      2017-03-07
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 脊椎損傷モデルラットにおけるFGF2処理ヒト歯髄細胞移植の回復促進効果:細胞・FGF2単独投与との比較2017

    • Author(s)
      杉山健、飯田一規、川口知子、畠山大二郎、柴田敏之、福光秀文、手塚健一
    • Organizer
      第16回日本再生医療学会総会
    • Place of Presentation
      仙台国際センター(仙台市)
    • Year and Date
      2017-03-07
    • Related Report
      2016 Annual Research Report
  • [Presentation] 再生医療資源としてのヒト歯髄細胞の有用性2017

    • Author(s)
      柴田敏之
    • Organizer
      第55回日本口腔科学会北日本地方部会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ヒト歯髄細胞における脊髄損傷後の回復効果を促進させるFGF2応答性遺伝子の検討2017

    • Author(s)
      杉山健、飯田一規、川口知子、畠山大二郎、柴田敏之
    • Organizer
      第62回日本口腔外科学会総会・学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The homeobox gene DLX4 promotes generation of human induced pluripotent srem cells2014

    • Author(s)
      T.Tamaoki, K Takahashi, H Aoki, K Iida, T Kawaguchi, D Hatakeyama, M Indan, N Chousa, A Isisaki, T Kunisada, T Shibata, N Gotou, S Yamanaka, K Tezuka
    • Organizer
      ASBMR(アメリカ骨代謝学会)
    • Place of Presentation
      テキサス州ヒューストン
    • Year and Date
      2014-09-12 – 2014-09-16
    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] Method for producing induced pluripotent stem cells2016

    • Inventor(s)
      SHIBATA Toshiyuki
    • Industrial Property Rights Holder
      SHIBATA Toshiyuki
    • Industrial Property Rights Type
      特許
    • Filing Date
      2016-01-16
    • Related Report
      2015 Annual Research Report
    • Overseas

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Published: 2014-04-04   Modified: 2020-03-30  

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