虚血性難聴に対する骨髄幹細胞を用いた再生治療の試み

• Project/Area Number: 19659437
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Otorhinolaryngology
• Research Institution: Ehime University
• Principal Investigator: 澤井 志保 (安藤 志保) Ehime University, 医学部附属病院, 専攻医 (90448374)
• Co-Investigator(Kenkyū-buntansha): 暁 清文 愛媛大学, 大学院・医学系研究科, 教授 (00108383) ; 秦 龍二 愛媛大学, 大学院・医学系研究科, 准教授 (90258153) ; 出崎 順三 愛媛大学, 大学院・医学系研究科, 講師 (00036451) ; 朱 鵬翔 愛媛大学, 大学院・医学系研究科, 助教 (40380216)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2008: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2007: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: Cochlear ischemia / Hematopoietic stem cell / Apoptosis / Regeneration

Research Abstract

虚血性難聴モデル動物に骨髄造血幹細胞を用いた再生治療を試みた。内耳虚血負荷を加えた砂ネズミに骨髄造血幹細胞を内耳に移植すると、聴性脳幹反応(ABR)の虚血性障害が有意に改善した。更に蝸牛を摘出し、有毛細胞の細胞死の有無を検討すると、幹細胞治療群で有意に内有毛細胞の虚血性細胞死が抑制されていた。次いで細胞死抑制機構における骨髄造血幹細胞の役割を検討するために、骨髄造血幹細胞を蛍光色素でラベリングし経時的に細胞動態を調べると、内耳に移植された骨髄造血幹細胞は鼓室階に留まっており、内有毛細胞に再分化したり、障害を受けた内有毛細胞と融合した骨髄造血幹細胞は見いだせなかった。従って内耳虚血障害では、骨髄造血幹細胞が有毛細胞に再分化したり障害有毛細胞と融合して、有毛細胞を再生する可能性はほとんどないと考えられた。一方幹細胞は多分化・自己再生能以外に各種栄養因子を分泌することが知られている。そこで各種栄養因子を調べてみると、骨髄造血幹細胞治療群の蝸牛では有意にglial cell line-derived neurotrophic factor (GDNF)のタンパク量が増大していることが明らかとなった。以上のことより、骨髄造血幹細胞は内有毛細胞に再分化したり、障害を受けた内有毛細胞と融合するのではなく、内耳でのGDNFの発現を増大させることで虚血性内耳障害を軽減させることが明らかとなった。今回の検討では残念ながら骨髄造血幹細胞からは有毛細胞の再生は認められなかった。そこで現在有毛細胞自身の再生を目指して、胚性幹細胞を用いた分化誘導実験を行っている。これに成功すれば有毛細胞を直接再生することが可能となり、再生治療の新たな手法を開発できるものと考えられる。

Research Products

• [Journal Article] Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function. (2008)
  • Author(s): Zhu P, Hata R, Cao F, Gu F, Hanakawa Y, Hashimoto K, Sakanaka M.
  • Journal Title: FASEB J 22 Pages: 3866-77
  • Peer Reviewed
• [Journal Article] Postischemic mild hypothermia alleviates hearing loss because of transient ischemia. (2008)
  • Author(s): Takeda S, Hakuba N, Yoshida T, Fujita K, Hato N, Hata R, Hyodo J, Gyo K
  • Journal Title: Neuroreport. 19 Pages: 1325-8
  • Peer Reviewed
• [Journal Article] A swallowing evaluation with simultaneous videoendoscopy, ultrasonography and videofluorography in healthy controls. (2008)
  • Author(s): Komori M, Hyodo M, Gyo K
  • Journal Title: ORL J Otorhinolaryngol Relat Spec. 70 Pages: 393-8
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor 1 treatment via hydrogels rescues cochlear hair cells from ischemic injury. (2008)
  • Author(s): Fujiwara T, Hato N, Nakagawa T, Tabata Y, Yoshida T, Komobuchi H, Takeda S, Hyodo J, Hakuba N, Gyo K.
  • Journal Title: Neuroreport. 19 Pages: 1585-8
  • Peer Reviewed
• [Journal Article] Valacyclovir for the treatment of Bell's palsy. (2008)
  • Author(s): Hato N, Sawai N, Teraoka M, Wakisaka H, Takahashi H, Hinohira Y, Gyo K.
  • Journal Title: Expert Opin Pharmacother. 9 Pages: 2531-6
  • Peer Reviewed
• [Journal Article] Steroid and antiviral treatment for Bell's palsy. (2008)
  • Author(s): Hato N, Murakami S, Gyo K
  • Journal Title: Lancet. 371 Pages: 1818-20
  • Peer Reviewed
• [Journal Article] Intravenous Infusion of Dihydroginsenoside Rb1 Prevents Compressive Spinal Cord Injury and Ischemic Brain Damage through Upregulation of VEGF and Bcl-xL (2007)
  • Author(s): Sakanaka M, Zhu P, Zhang Bo, Wen TC, Cao F, Ma YJ, Samukawa K, Mitsuda N, Tanaka J, Kuramoto M, Uno H, Hata R.
  • Journal Title: Journal of Neurotrauma 24 Pages: 1037-1054
  • Peer Reviewed
• [Journal Article] Hematopoietic stem cells prevent hair cell death after transient cochlear ischemia through paracrine effects (2007)
  • Author(s): Yoshida T, Hakuba N, Morizane I, Fujita K, Cao F, Zhu P, Uchida N, Kameda K, SakanakaM, Gyo, K, Hata R
  • Journal Title: Neuroscience 145 Pages: 923-930
  • Peer Reviewed
• [Journal Article] Ginsenoside Rb 1 protects against damage to the spiral ganglion cells after cochlear ischemia (2007)
  • Author(s): Fujita K, Hakuba N, Hata R, Morizane I, Yoshida T, Shudou M, Sakanaka M, and Gyo K
  • Journal Title: Neurosci Lett 415 Pages: 113-117
  • Peer Reviewed
• [Presentation] Hematopoietic stem cells prevent hair cell death after transient cochlear ischemia through paracrine effects (2007)
  • Author(s): Yoshida T, Hata R, Hakuba N, Cao F, Zhu P, Sakanaka M, Gyo K.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Fungtion
  • Place of Presentation: Osaka,Japan
• [Presentation] Protective effects of dihydrogeninsenoside Rb1 on ischemic brain damage and compressive spinal cord injury through upregulation of VEGF and Bcl-XL (2007)
  • Author(s): Hata R, Cao F, Zhu P, Samukawa K, Sakanaka M.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka,Japan
• [Presentation] Overexpression of Stat3 promotes neuronal cell death through activation of microglia (2007)
  • Author(s): Hata R, Cao F, Zhu P, Sakanaka M.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka,Japan
• [Presentation] Microglia promotes astrogliogenesis of the neural stem cells through activating Jak/Stat signahng (2007)
  • Author(s): Zhu P, Hata R, Cao F, Sakanaka M.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka,Japan
• [Presentation] Upregulation of syntaxin1 in the ischemic cortex following permanent focal ischemia in rats (2007)
  • Author(s): Cao F, Hata R, Zhu P, Sakanaka M.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka,Japan
• [Presentation] Targeted disruption of organic cation transporter 3 in mice reducesischemic brain injury through down-regulation of IL-6 and MCP-1 (2007)
  • Author(s): Zhu P, Hata R, Ogasawara M, Cao F, Maeyama K, Sakanaka M.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka,Japan
• [Presentation] Delayed neuronal cell death in the brain stem after transient ischemia in gerbils (2007)
  • Author(s): Cao F, Hata R, Zhu P, Sakanaka M.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka,Japan
• [Presentation] α-synuclein promotes neuronal cell death through the activation of microglia (2007)
  • Author(s): Hata R, Zhu P, Cao F, Sakanaka M, Tanabe H.
  • Organizer: International Psychogeriatric Association 25th Anniversary Meeting
  • Place of Presentation: Osaka,Japan
• [Presentation] Risk of conversion from mild memory impairment to Altzhemier'disease in a Japanese community(from the Nakayama Study) (2007)
  • Author(s): Matsumoto N, Hata R, IshikawaT, Fukuhara R, Hokoishi K, Ikeda M, Tanabe H.
  • Organizer: International Psychogeriatric Association 25th Anniversary Meeting
  • Place of Presentation: Osaka,Japan