The effects of SOCS3 on neural stem cell fate and feasibility of the SOCS3-overexpressingneural stem cells for stake therapy

• Project/Area Number: 18591594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Ehime University
• Principal Investigator: HATA Ryuji Ehime University, Graduate School of Medicine, Associate Professor (90258153)
• Co-Investigator(Kenkyū-buntansha): ONISHI Takanori Ehime University, Graduate School of Medicine, Professor (70233210) ; KUMON Yoshiaki Ehime University, Graduate School of Medicine, Associate Professor (80127894) ; TANAKA Jyunya Ehime University, Graduate School of Medicine, Professor (70217040)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: SOCS3 / Cerebral ischemia / Neurogenesis / Neural stem cell / Neurogenesis / cerebral ischemia / neurogenesis / neural stem cell

Research Abstract

To investigate the effects of suppressors of cytokine signaling 3 (SOCS3) on neural stem cell fate, stem cells were infected with an adenoviral vector expressing SOCS3. Three days later, western blot analysis and immunocytochemical analysis revealed that the protein level of MAP2 and the number of MAP2-positive cells were significantly increased in SOCS3-transfected cells, while the protein level of GFAP and the number of GFAP-positive cells were significantly decreased. Furthermore, promoter assay revealed a significant reduction in the transcriptional level of signal transducer and activator of transcription 3 (Stat3) in the transfected cells. In addition, the mRNA levels of Notch family member (notchl) and inhibitory bHLH factors (hes5 and id3) were significantly up-regulated at one day after overexpression of SOCS3. At three days after transfection, the mRNA level of hes5 was significantly decreased, while that of notchl was still up-regulated. Moreover, all of SOCS3-positive cells expressed Nestin protein but did not express both MAP2 and GFAP proteins. These data indicate that overexpression of SOCS3 induced neurogenesis and inhibited astrogliogenesis in neural stem cells. Our data also show that SOCS3 promoted maintenance of neural stem cells. Furthermore, we evaluated the feasibility of the SOCS3-overexpressing neural stem cells for stroke therapy. Rats were subjected to focal cerebral ischemia for 60 min. Following reperfusion, neural stem cells over-expressing SOCS3 (1.0 x 10^5/5ul) were injected into common carotid artery. One day later, we evaluated the infarct size by TTC staining. However, there was no difference in infarct volume between the SOCS3-treated group and vehicle-treated group. We are now trying to evaluate other methods to transplant NSC into the brain, although we failed to demonstrate the feasibility SOCS3-overexpressing neural stem cells for stroke therapy this time.

Research Products

• [Journal Article] Intravenous Infusion of Dihydroginsenoside Rbl 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 TG, 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
  • Description: 「研究成果報告書概要(和文)」より
  • 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, Sakanaka M, Gyo K, Hata R
  • Journal Title: Neuroscience 145 Pages: 923-930
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Ginsenoside Rbl 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
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intravenous Infusion of Dihydroginsenoside Rbl 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
  • Description: 「研究成果報告書概要(欧文)」より
• [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., Sakanaka, M., Gyo, K., Hata, R
  • Journal Title: Neuroscience 145 Pages: 923-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ginsenoside Rb1 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., Gyo, K
  • Journal Title: Neurosci Lett 415 Pages: 113-7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intravenous Infusion of Dihydroginsenoside Rb 1 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] 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
• [Journal Article] Ginsenoside Rb1 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, Gyo K.
  • Journal Title: Neurosci Lett. 415 Pages: 113-7
• [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, Sakanaka M, Gyo K, Hata R.
  • Journal Title: Neuroscience 145 Pages: 923-30
• [Journal Article] Prevention of ischemic neuronal death by intravenous infusion of aginseng saponin,ginsenoside Rb(1),that upregulates Bcl-x(L)expression (2006)
  • Author(s): Zhang B, Hata R, Zhu P, Sato K, Wen TC, Yang L, Fujita H, Mitsuda N, Tanaka J, Samukawa K, Maeda N, and Sakanaka M.
  • Journal Title: J Cereb Blood Flow Metab 26 Pages: 708-721
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells (2006)
  • Author(s): Cao F, Hata R, Zhu P, Ma YJ, Tanaka J, Hanakawa Y, Hashimoto K, Niinobe M, Yoshikawa K and Sakanaka M.
  • Journal Title: J Neurochem. 98 Pages: 459-70
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells (2006)
  • Author(s): Cao, F., Hata, R., Zhu, P., Ma, YJ., Tanaka, J., Hanakawa, Y., Hashimoto, K., Niinobe, M., Yoshikawa, K., Sakanaka, M
  • Journal Title: J Neurochem 98 Pages: 459-70
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prevention of ischemic neuronal death by intravenous infusion of a ginseng saponin, ginsenoside Rb(1), that upregulates Bcl-x(L) expression (2006)
  • Author(s): Zhang, B., Hata, R., Zhu, P., Sato, K., Wen, TC., Yang, L., Fujita, H., Mitsuda, N., Tanaka, J., Samukawa, K., Maeda, N., Sakanaka, M
  • Journal Title: J Cereb Blood Flow Metab 26 Pages: 708-721
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prevention of ischemic neuronal death by intravenous infusion of a ginseng saponin, ginsenoside Rb(1), that upregulates Bcl-x(L) expression. (2006)
  • Author(s): Zhang B, Hata R, Zhu P, Sato K, Wen TC, Yang L, Fujita H, Mitsuda N, Tanaka J, Samukawa K, Maeda N, Sakanaka M.
  • Journal Title: J Cereb Blood Flow Metab 26 Pages: 708-721
• [Journal Article] Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells. (2006)
  • Author(s): Cao F, Hata R, Zhu P, Ma YJ, Tanaka J, Hanakawa Y, Hashimoto K, Niinobe M, Yoshikawa K, Sakanaka M.
  • Journal Title: J Neurochem. 98 Pages: 459-70
• [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 & Function
  • Place of Presentation: Osaka, Japan
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Microglia promotes astrogliogenesis of the neural stem cells through activating Jak/Stat signaling. (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
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Upregulation of syntaxinl 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
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Targeted disruption of organic cation transporter 3 in mice reduces ischemic brain injury through down-regula tion 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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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, Ishikawa T, Fukuhara R, Hokoishi K, Ikeda M, Tanabe H.
  • Organizer: International Psychogeriatric Association 25th Anniversary Meeting
  • Place of Presentation: Osaka, Japan
  • Description: 「研究成果報告書概要(和文)」より
• [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 & Function
  • Place of Presentation: Osaka
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Protective effects of dihydrogeninsenoside Rbl 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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Microglia promotes astrogliogenesis of the neural stem cells through activating Jak/Stat signaling (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
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Upregulation of syntaxinl 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
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Targeted disruption of organic cation transporter 3 in mice reduces ischemic 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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [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., Ishikawa, T., Fukuhara, R., Hokoishi, K., Ikeda, M., Tanabe, H
  • Organizer: International Psychogeriatric Association 25th Anniversary Meeting
  • Place of Presentation: Osaka
  • Description: 「研究成果報告書概要(欧文)」より
• [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&Function
  • Place of Presentation: Osaka,Japan
• [Presentation] Protective effects of dihydrogeninsenoside Rb 1 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 Stat 3 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 signaling (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 syntaxin 1 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 reduces ischemic 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'd isease in a Japanese community(from the Nakayama Study). (2007)
  • Author(s): Matsumoto N, Hata R, Ishikawa T, Fukuhara R, Hokoishi K, Ikeda M, Tanabe H.
  • Organizer: International Psychogeriatric Association 25th Anniversary Meeting
  • Place of Presentation: Osaka,Japan