Inner ear stem cell therapy with acivation of stem cell homing

• Project/Area Number: 25462653
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Juntendo University
• Principal Investigator: Kamiya Kazusaku 順天堂大学, 医学部, 准教授 (10374159)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 蝸牛 / 細胞治療 / 幹細胞ホーミング / 遺伝性難聴 / 難聴モデル動物 / コネキシン26 / 内耳細胞治療 / 再生医療 / 蝸牛線維細胞 / 間葉系幹細胞 / 多能性幹細胞 / コネキシン２６ / ギャップジャンクション

Outline of Final Research Achievements

Inner ear cell therapy for sensorineural hearing loss has been expected to be an effective therapy for hereditary deafness. Previously, we developed a novel strategy for inner ear cell therapy using bone marrow mesenchymal stem cells as a supplement for cochlear fibrocytes functioning for cochlear ion transport. For cell therapy targeting hereditary deafness, a more effective cell delivery system to induce the stem cells into cochlear tissue is required, because gene mutations affect all cochlear cells cochlear cells expressing genes such as GJB2 encoding CX26. Stem cell homing is one of the crucial mechanisms to be activated for efficient cell delivery to the cochlear tissue. In our study, monocyte chemotactic protein-1, stromal cell-derived factor-1 and their receptors were found to be a key regulator for stem cell recruitment to the cochlear tissue.

Research Products

• [Journal Article] Deformation of the Outer Hair Cells and the Accumulation of Caveolin-2 in Connexin 26 Deficient Mice. (2015)
  • Author(s): Anzai, T., Fukunaga, I., Hatakeyama, K., Fujimoto, A., Kobayashi, K., Nishikawa, A., Aoki, T., Noda, T., Minowa, O., Ikeda, K., and Kamiya, K
  • Journal Title: PloS one Volume: 10 Issue: 10 Pages: e0141258-e0141258
  • DOI: 10.1371/journal.pone.0141258
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Postnatal Development and Maturation of the Vestibular Organ in Dominant-Negative Connexin 26 Transgenic Mouse. (2015)
  • Author(s): Hiroko Okada, Kazusaku Kamiya., Takashi Iizuka and Katsuhisa Ikeda.
  • Journal Title: J Otol Rhinol Volume: S1 Pages: 37-40
  • DOI: 10.4172/2324-8785.s1-009
  • Peer Reviewed / Open Access
• [Journal Article] Differentiation of iPS Cells to Cochlear Cells are Regulated Depending on the Part of Co-cultured Organs. (2015)
  • Author(s): Kazusaku Kamiya, Keiko Karasawa, Kazuma Kobayashi, Asuka Miwa and Katsuhisa Ikeda.
  • Journal Title: J Otol Rhinol Volume: S1 Pages: 34-36
  • DOI: 10.4172/2324-8785.s1-008
  • Peer Reviewed / Open Access
• [Journal Article] Perinatal Gjb2 gene transfer rescues hearing in a mouse model of hereditary deafness. (2015)
  • Author(s): Izuka T., Kamiya K., Gotoh S., Sugitani Y., Suzuki M., Noda T., Minowa O., Ikeda K.
  • Journal Title: Hum. Mol.Genet. Volume: 24)13) Issue: 13 Pages: 3651-3661
  • DOI: 10.1093/hmg/ddv109
  • Peer Reviewed / Open Access
• [Journal Article] Connexin26 regulates assembly and maintenance of cochlear gap junction macromolecular complex for normal hearing (2015)
  • Author(s): Kazusaku Kamiya, Ichiro Fukunaga, Kaori Hatakeyama and Katsuhisa Ikeda
  • Journal Title: AIP Conference Proceedings Volume: 1703 Pages: 030018-030018
  • DOI: 10.1063/1.4939333
  • Acknowledgement Compliant
• [Journal Article] Assembly of the cochlear gap junction macromolecular complex requires connexin 26. (2014)
  • Author(s): Kamiya K, Yum SW, Kurebayashi N, Muraki M, Ogawa K, Karasawa K, Miwa A, Guo X, Gotoh S, Sugitani Y, Yamanaka H, Ito-Kawashima S, Iizuka T, Sakurai T, Noda T, Minowa O, Ikeda K.
  • Journal Title: J Clin Invest, Volume: 124 Issue: 4 Pages: 1598-1607
  • DOI: 10.1172/jci67621
  • Peer Reviewed / Open Access
• [Journal Article] Dominant negative connexin26 mutation R75W causing severe hearing loss influences normal programmed cell death in postnatal organ of Corti (2014)
  • Author(s): Ayako Inoshita, Keiko Karasawa, Megumi Funakubo, Asuka Miwa, Katsuhisa Ikeda, Kazusaku Kamiya
  • Journal Title: BMC genetics Volume: 15(1) Issue: 1 Pages: 1-8
  • DOI: 10.1186/1471-2156-15-1
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type caused by mutated Bsnd in mice. (2013)
  • Author(s): Nomura N, Kamiya K, Ikeda K, Yui N, Chiga M, Sohara E, Rai T, Sasaki S, Uchida S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 441 Issue: 3 Pages: 544-49
  • DOI: 10.1016/j.bbrc.2013.10.129
  • Peer Reviewed
• [Journal Article] 遺伝性難聴への内耳細胞治療法開発 Cell therapy for hereditary hearing loss with stem cell homing factors. (2013)
  • Author(s): 神谷和作
  • Journal Title: 日本薬理学雑誌 Volume: 141(4) Pages: 191-4
  • Peer Reviewed
• [Presentation] GJB2変異遺伝性難聴に対する細胞治療・遺伝子治療法の開発 (2016)
  • Author(s): 神谷 和作
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2016-03-17
• [Presentation] iPS細胞からのConnexin26発現細胞への分化誘導と細胞間ギャップ結合プラークの構築 (2016)
  • Author(s): 福永一朗、畠山佳欧里、 青木徹、藤本あゆみ、 西川貴菜、美野輪治、 池田勝久、神谷和作
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2016-03-17
• [Presentation] コネキシン26欠損マウスからのiPS細胞の樹立 (2016)
  • Author(s): 青木徹、福永一朗、 畠山佳欧里、藤本あゆみ、西川貴菜、美野輪治、 池田勝久、神谷和作
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2016-03-17
• [Presentation] 内耳フィーダー細胞を用いたiPS細胞の分化誘導によるCx26ギャップ結合形成細胞の樹立 (2016)
  • Author(s): 藤本あゆみ、福永一朗、 畠山佳欧里、青木徹、 西川貴菜、池田勝久、 神谷和作
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2016-03-17
• [Presentation] Restoration og Cochlear Gap Junction for GJB2 (2016)
  • Author(s): Kazusaku Kamiya, Ichiro Fukunaｇa
  • Organizer: Association for Research in Otolaryngology (ARO), 39th Annual MidWinter Meeting
  • Place of Presentation: Manchester Grand Hyatt, San Diego, CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Deformation of the Outer Hair Cells and the Accumulation of Caveolin-2 in Connexin 26-Deficient Mice (2016)
  • Author(s): Takashi Anzai, Kazusaku Kamiya, Katsuhisa Ikeda
  • Organizer: Association for Research in Otolaryngology (ARO), 39th Annual MidWinter Meeting
  • Place of Presentation: Manchester Grand Hyatt, San Diego, CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Generation of induced pluripoten stem cells form connexin26 conditional knock out mouce (2016)
  • Author(s): Toru Aoki, Katsuhisa Ikeda, Kazusaku Kamiya
  • Organizer: Association for Research in Otolaryngology (ARO), 39th Annual MidWinter Meeting
  • Place of Presentation: Manchester Grand Hyatt, SanDiego,CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Differentiation of mouse iPS cell into Cx26-positive cell and formation of inter cellular Cx26-gap junction plaque (2016)
  • Author(s): Ichiro Fukunaga, Kaori Hatakeyama,Toru Aoki, Atena Nishikawa, Ayumi Fujimoto, Katsuhisa Ikeda, Kazusaku Kamiya
  • Organizer: Association for Research in Otolaryngology (ARO), 39th Annual MidWinter Meeting
  • Place of Presentation: Manchester Grand Hyatt, SanDiego,CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Induction of iPS cell differentiation into Connexin26 positive cells with gap junction plaques using cochlear feeder cell (2016)
  • Author(s): Ayumi Fujimoto, Ichiro Fukunaga, Kaori Hatakeyama, Toru Aoki, Atena Nishikawa, Katsuhisa Ikeda, Kazusaku Kamiya
  • Organizer: Association for Research in Otolaryngology (ARO), 39th Annual MidWinter Meeting
  • Place of Presentation: Manchester Grand Hyatt, SanDiego,CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Various cochlear gap junction plaque reproduced in human cell line (2016)
  • Author(s): Kaori Hatakeyama, Katsuhisa Ikeda, Kazusaku Kamiya
  • Organizer: Association for Research in Otolaryngology (ARO), 39th Annual MidWinter Meeting
  • Place of Presentation: Manchester Grand Hyatt, SanDiego,CA, USA
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Cochlear gap junction plaque, stabilized macromolecular complex composed of specific connexins (2015)
  • Author(s): Kazusaku Kamiya, Ichiro Fukunaga, Kaori Hatakeyama, Toru Aoki, Ayumi Fujimoto, Atena Nishikawa ,Takashi Anzai, Osamu Minowa, Katsuhisa Ikeda
  • Organizer: 52nd Inner Ear Biology Workshop
  • Place of Presentation: Campus of the Catholic University of Rome, Italy
  • Year and Date: 2015-09-12
  • Int'l Joint Research
• [Presentation] Caveolins accumulates at the organ of Corti in GJB2 associated deafness (2015)
  • Author(s): Takashi Anzai, Kazusaku Kamiya, Katsuhisa Ikeda
  • Organizer: 52nd Inner Ear Biology Workshop
  • Place of Presentation: Campus of the Catholic University of Rome, Italy
  • Year and Date: 2015-09-12
  • Int'l Joint Research
• [Presentation] Reproduction of various types of cochlear gap junction plaques in human cell line (2015)
  • Author(s): Kaori Hatakeyama, Katsuhisa Ikeda, Kazusaku Kamiya
  • Organizer: 52nd Inner Ear Biology Workshop
  • Place of Presentation: Campus of the Catholic University of Rome, Italy
  • Year and Date: 2015-09-12
  • Int'l Joint Research
• [Presentation] Differentiation of mouse iPS cell into Cx26-positive cell and formation of inter cellular Cx26-gap junction plaque (2015)
  • Author(s): Ichiro Fukunaga, Kaori Hatakeyama,Toru Aoki, Atena Nishikawa, Ayumi Fujimoto, Osamu Minowa, Katsuhisa Ikeda, Kazusaku Kamiya
  • Organizer: 52nd Inner Ear Biology Workshop
  • Place of Presentation: Campus of the Catholic University of Rome, Italy
  • Year and Date: 2015-09-12
  • Int'l Joint Research
• [Presentation] The activation of stem cell homing factors highly induce the cochlear invasion of bone marrow mesenchymal stem cells. (2014)
  • Author(s): Kazusaku Kamiya, Keiko Karasawa, Asuka Miwa, Osamu Minowa, Megumi Funakubo1, Katsuhisa Ikeda
  • Organizer: Association for Research in Otolaryngology (ARO), 37th MidWinter Meeting
  • Place of Presentation: 米国 サンディエゴ
• [Presentation] 幹細胞ホーミング分子機構を応用した効率的内耳細胞治療法の開発 (2013)
  • Author(s): 神谷和作 美野輪治 池田勝久
  • Organizer: 第23回 日本耳科学会学術集会
  • Place of Presentation: 宮崎県