Multipotential stem cell-like nature of bone marrow-derived macrophages accumulated in lesion core of acute and severe brain injuries.

• Project/Area Number: 22390037
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Ehime University
• Principal Investigator: TANAKA Junya 愛媛大学, プロテオ医学研究センター, 教授 (70217040)
• Co-Investigator(Kenkyū-buntansha): YANO Hajime 愛媛大学, 大学院・医学系研究科, 准教授 (00284414) ; TAKAHASHI Hisaaki 愛媛大学, 医学部附属病院, 講師 (20363228) ; SUGIMOTO Kana 愛媛大学, 大学院・医学系研究科, 助教 (00581034)
• Co-Investigator(Renkei-kenkyūsha): OHNISHI Takanori 愛媛大学, 大学院・医学系研究科, 教授 (70233210) ; KUMON Yoshiaki 愛媛大学, 大学院・医学系研究科, 准教授 (80127894)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: マクロファージ / マイクログリア / 骨髄 / 分化多能性 / 神経細胞保護作用 / 単球 / BINCs / 脳梗塞 / NG2 / パーキンソン病 / 新規治療法 / 幹細胞性 / 脳損傷 / Iba1 / サイトカイン / 分化誘導

Research Abstract

Many bone marrow-derived macrophages were found to accumulate in lesion cores of stroke and traumatic brain injuries. Because most of the cells expressed a multipotent cell marker in the brain, NG2 chondroitin sulfate proteoglycan as well as a macrophage marker Iba1, they were termed BINCs (Brain Iba1^+/NG2^+Cells). BINCs exerted neuroprotective actions and promoted regeneration and restoration of injured tissue by releasing neuroprotective growth factors and scavenging degenerated cellsand tissues. We found that injection of a cytokine mixture (IL3 and GM-CSF) markedly ameliorated traumatic brain injury and Parkinson’s disease.

Research Products

• [Journal Article] Expression of MCP-1 and fractalkine on endothelial cells and astrocytes may contribute to the invasion and migration of brain macrophages in ischemic rat brain lesions (2013)
  • Author(s): Nari Tei, Junya Tanaka, Kana Sugimoto, Tasuku Nishihara, Ryutaro Nishioka, Hisaaki Takahashi, Hajime Yano, Shirabe Matsumoto, Shiro Ohue, Hideaki Watanabe, Yoshiaki Kumon, Takanori Ohnishi
  • Journal Title: J Neurosci Res Volume: 91 Pages: 681-693
  • Peer Reviewed
• [Journal Article] Expression of MCP-1 and fractalkine on endothelial cells and astrocytes may contribute to the invasion and migration of brain macrophages in ischemic rat brain lesions (2013)
  • Author(s): Nari Tei
  • Journal Title: J Neurosci Res Volume: 91 Issue: 5 Pages: 681693-681693
  • DOI: 10.1002/jnr.23202
  • Peer Reviewed
• [Journal Article] Anticonvulsive effect of paeoniflorin on experimental febrile seizures in immature rats: possible application for febrile seizures in children (2012)
  • Author(s): Hitomi Hino, Hisaaki Takahashi, Yuka Suzuki, Junya Tanaka, Eiichi Ishii, Mitsumasa Fukuda
  • Journal Title: PLoS ONE Volume: 7 Issue: 8 Pages: e42920-e42920
  • DOI: 10.1371/journal.pone.0042920
  • Peer Reviewed
• [Journal Article] Zonisamide up-regulated them RNAs encoding astrocytic anti-oxidative and neurotrophic factors (2012)
  • Author(s): Choudhury ME, Sugimoto K, Kubo M, Iwaki H, Tsujii T, Kyaw WT, Nishikawa N, Nagai M, Tanaka J, Nomoto M
  • Journal Title: Eur J Pharmacol Volume: 689 Pages: 72-80
  • Peer Reviewed
• [Journal Article] Premetastatic vasculogenesis in oral squamous cell carcinoma xenograft-draining lymph nodes. (2012)
  • Author(s): Mayorca-Guiliani AE, Yano H, Nakashiro KI, Hamakawa H, Tanaka J.
  • Journal Title: Oral Oncology Volume: 48 Pages: 663-670
  • Peer Reviewed
• [Journal Article] Oct-3/4 promotes migration and invasion of glioblastoma cells. (2012)
  • Author(s): Kobayashi K, Takahashi H, Inoue A, Harada H, Toshimori S, Kobayashi Y, Goto K, Sugimoto K, Yano H, Ohnishi T, Tanaka J.
  • Journal Title: J Cell Biochem Volume: 113 Pages: 508-517
  • Peer Reviewed
• [Journal Article] Zonisamide up-regulated them RNAs encoding astrocytic anti-oxidative and neurotrophic factors (2012)
  • Author(s): Choudhury ME
  • Journal Title: Eur J Pharmacol Volume: 689 Issue: 1-3 Pages: 7280-7280
  • DOI: 10.1016/j.ejphar.2012.05.012
  • Peer Reviewed
• [Journal Article] Premetastatic vasculogenesis in oral squamous cell carcinoma xenograft-draining lymph nodes (2012)
  • Author(s): Mayorca-Guiliani AE
  • Journal Title: Oral Oncology Volume: 48 Issue: 8 Pages: 663670-663670
  • DOI: 10.1016/j.oraloncology.2012.02.007
  • Peer Reviewed
• [Journal Article] Oct-3/4 promotes migration and invasion of glioblastoma cells (2012)
  • Author(s): Kobayashi K
  • Journal Title: J Cell Biochem Volume: 113 Issue: 2 Pages: 508517-508517
  • DOI: 10.1002/jcb.23374
  • Peer Reviewed
• [Journal Article] Transient ischemia-induced paresis and complete paraplegia displayed distinct reactions of microglia and macrophages. (2011)
  • Author(s): NakataT, Kawachi K, Nagashima M, Yasugi T, Izutani H, Ryugo M, Okamura T, Shikata F, Imagawa H, Yano H, Takahashi H, Tanaka J.
  • Journal Title: Brain Res Volume: 1420 Pages: 114-124
  • Peer Reviewed
• [Journal Article] A cytokine mixture of GM‐CSF and IL‐3 that induces a neuroprotective phenotype of microglia leading to amelioration of (6‐OHDA)‐induced Parkinsonism of rats (2011)
  • Author(s): Choudhury ME, Sugimoto K, Kubo M, Nagai M, Nomoto M, Takahashi H, Yano H, Tanaka J.
  • Journal Title: Brain Behav Volume: 1 Pages: 26-43
  • Peer Reviewed
• [Journal Article] Subcutaneous injection containing IL-3 and GM-CSF ameliorates stab wound-induced brain injury in rats. Tasuku (2011)
  • Author(s): Hisaaki Takahashi, Hajime Yano, Yoshiaki Kumon, Takanori Ohnishi, Junya Tanaka.
  • Journal Title: Exp Neurol Volume: 229 Pages: 507-516
  • Peer Reviewed
• [Journal Article] Subcutaneous injection containing IL-3 and GM-CSF ameliorates stab wound-induced brain injury in rats (2011)
  • Author(s): Nishihara, T., et al
  • Journal Title: Experimental neurology Volume: 229 Issue: 2 Pages: 507-516
  • DOI: 10.1016/j.expneurol.2011.04.006
  • Peer Reviewed
• [Journal Article] Transient ischemia-induced paresis and complete paraplegia displayed distinct reactions of microglia and macrophages (2011)
  • Author(s): Nakata, T., et al
  • Journal Title: Brain research Volume: 1420 Pages: 114-124
  • DOI: 10.1016/j.brainres.2011.08.074
  • Peer Reviewed
• [Journal Article] A cytokine mixture of GM-CSF and IL-3 that induces a neuroprotective phenotype of microglia leading to amelioration of (6-OHDA)-induced Parkinsonism of rats (2011)
  • Author(s): Choudhry, E., et al
  • Journal Title: Brain and Behavior Volume: 1 Issue: 1 Pages: 26-43
  • DOI: 10.1002/brb3.11
  • Peer Reviewed
• [Journal Article] Subcutaneous injection containing IL-3 and GM-CSF amelioratesstab wound-induced brain injury in rats (2011)
  • Author(s): Nishihara T, Michihisa Ochi M, Kana Sugimoto K, Takahashi H, Yano H, Kumon Y, Ohnishi T, Tanaka J
  • Journal Title: Experimental Neurology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cancer stem-like cells of glioblastoma characteristically express MMP-13 and display highly invasive activity. (2010)
  • Author(s): Inoue, A., Takahashi, H., Harada, H., Kohno, S., Ohue, S., Kobayashi, K., Yano, H., Tanaka, J., Ohnishi, T.
  • Journal Title: Int J Oncol Volume: 37 Pages: 1121-1131
  • Peer Reviewed
• [Journal Article] Iba1+/NG2+ macrophage-like cells expressing a variety of neuroprotective factors ameliorate ischemic damage of the brain. (2010)
  • Author(s): Anna Smirkin, Hiroaki Matsumoto, Hisaaki Takahashi, Akihiro Inoue, Masahiko Tagawa, Shiro Ohue, Hideaki Watanabe, Hajime Yano, Yoshiaki Kumon, Takanori Ohnishi and Junya TanakaJ
  • Journal Title: J Cereb Blood Flow Metab Volume: 30 Pages: 603-615
  • Peer Reviewed
• [Journal Article] Iba1(+)/NG2(+) macrophage-like cells expressing a variety of neuroprotective factors ameliorate ischemic damage of the brain (2010)
  • Author(s): Smirkin, A.Matsumoto, H.Takahashi, H.Inoue, A.Tagawa, M.Ohue, S.Watanabe, H.Yano, H.Kumon, Y.Ohnishi, T.Tanaka, J.
  • Journal Title: Journal of Cerebral Blood Flow and Metabolism Volume: 30 Pages: 603-615
  • Peer Reviewed
• [Journal Article] Cancer stem-like cells of glioblastoma characteristically express MMP-13 and display highly invasive activity (2010)
  • Author(s): Inoue A., Takahashi, H., Harada, H., Kohno, S., Ohue, S., Kobayashi, K., Yano, H., Tanaka, J., Ohnishi, T.
  • Journal Title: International journal of oncology Volume: 37 Pages: 1121-1131
  • Peer Reviewed
• [Presentation] Agents modulating neuroprotective and neurotoxic functions of microglia and their application to the pathologic brains Junya Tanaka (2013)
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京都
• [Presentation] Response of glial cells in and around ischemic lesion of rats that were subjected to transient middle cerebral artery occlusion: the involvement of IL-18 Ayano Mise (2013)
  • Author(s): Kana Sugimoto, Ryutaro Nishioka, Hisaaki Takahashi, Hajime Yano, Junya Tanak
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京都
• [Presentation] Invasion of monocytes/macrophages into ischemic lesion of rat brain: involvement of chemokines and their receptors (2013)
  • Author(s): Yudai Ohara, Kana Sugimoto, Ryutaro Nishioka, Hisaaki Takahashi, Hajime Yano、Nari Tei, Yoshiaki Kumon, Takanori Ohnishi, Junya Tanaka
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京都
• [Presentation] Agents modulating neuroprotective and neurotoxic functions of microglia and their application to the pathologic brains (2013)
  • Author(s): Junya Tanaka
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Response of glial cells in and around ischemic lesion of rats that were subjected to transient middle cerebral artery occlusion: the involvement of IL-18 (2013)
  • Author(s): Ayano Mise
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
• [Presentation] Invasion of monocytes/macrophages into ischemic lesion of rat brain: involvement of chemokines and their receptors (2013)
  • Author(s): Yudai Ohara
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
• [Presentation] Microglial cells expressing NG2 chondroitin sulfate proteoglycan in ischemic brain lesions of rats (2012)
  • Author(s): 杉本香奈, 他
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 長野県松本市
  • Year and Date: 2012-03-30
• [Presentation] A cytokine mixture containing GM-CSF and IL-3 targeting microglia ameliorates neurological deficits of Parkinson's disease model rats (2012)
  • Author(s): Junya Tanaka, Mohammed E. Choudhury, Kana Sugimoto, Hisaaki Takahashi, Hajime Yano
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本市
• [Presentation] 脳梗塞巣に集積するマクロファージの役割とその治療的利用 (2012)
  • Author(s): 田中潤也、杉本香奈、西原佑、高橋寿明、矢野元
  • Organizer: 第22回日本病態生理学会
  • Place of Presentation: 大分県由布市
• [Presentation] 神経細胞傷害に対するグリア細胞の反応:ラット6-OHDA負荷パーキンソン病モデルを用いた検討 (2011)
  • Author(s): 田中潤也, 他
  • Organizer: 第21回日本病態生理学会大会
  • Place of Presentation: 東京都板橋区
  • Year and Date: 2011-08-20
• [Presentation] Generation of ramified microglia and other types of neural cells from leptomeninges (2010)
  • Author(s): Kana Sugimoto, Hisaaki Takahashi, Hajime Yano, Junya Tanaka
  • Organizer: Neuro2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-02
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/kisogp/contents/laboratories
• [Remarks] 愛媛大学 kisogp 研究室紹介
  • URL: http://www.m.ehime-u.ac.jp/school/kisogp/contents/laboratories
• [Remarks]
  • URL: http://www.proteo.ehime-u.ac.jp/
• [Remarks]
  • URL: http://www.proteo.ehime-u.ac.jp/
• [Patent(Industrial Property Rights)] 免疫細胞の活性化抑制剤およびその用途 (2012)
  • Inventor(s): 田中潤也
  • Industrial Property Rights Holder: 国立大学法人愛媛大学
  • Industrial Property Number: 2012-173405
  • Filing Date: 2012-08-03