Therapeutic mechanisms of chronic pain by dental pulp stem cells

• Project/Area Number: 16K11477
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Nihon University (2019); Kyushu University (2016-2018)
• Principal Investigator: HAYASHI Yoshinori 日本大学, 歯学部, 助教 (80582717)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: カテプシンE / 好中球 / 一次求心性神経 / 慢性疼痛 / 機械的アロディニア / 神経障害性疼痛 / ヒト乳歯歯髄幹細胞 / 歯髄幹細胞 / 脊髄後根神経節

Outline of Final Research Achievements

The effects of dental pulp stem cells on chronic pain was found to be suppression of immune cells accumulating in the cell bodies of primary afferent fibers which transmit nociceptive information from the peripheral tissue to the spinal dorsal horn. Neutrophils were accumulated in response to induction of chemokine (C-X-C motif) ligand 1 (CXCL1), a kind of chemokine, in dorsal root ganglion neurons. Adoptive transferred activated wild-type but not cathepsin E-deficient neutrophils elicited mechanical allodynia in naive mice. Pro-elastase was cleaved within neutrophils in a cathepsin E-dependent manner. Elastase released from neutrophils could cause facilitation of neuronal activity via protease activated receptor 2. Activation of neutrophils was mediated through toll-like receptor 4.

Academic Significance and Societal Importance of the Research Achievements

神経障害性疼痛は既存の鎮痛薬ですら効果が乏しい症状である。そのため，新たな鎮痛薬開発が望まれている。多くの研究が行われているにも関わらず，神経障害性疼痛のメカニズムおよび治療法は未だ十分に明らかにされていない。このような中，神経障害性疼痛の治療方法としての幹細胞の意義を提示することができた。また，免疫細胞を介したメカニズムも明らかにすることができた。これらの情報を基に，今後新たな治療方法の開発への応用に繋げることができる可能性を提示できたと考える。

Research Products

• [Journal Article] Involvement of TNFα in the enhancement of hypersensitivity in the adulthood-injured face associated with facial injury in infancy (2020)
  • Author(s): Soma Kumi、Shinoda Masamichi、Hayashi Yoshinori、Kanno Kohei、Shirakwa Tetsuo、Iwata Koichi
  • Journal Title: Neuroscience Research Volume: - Pages: 30657-1
  • DOI: 10.1016/j.neures.2019.12.014
  • Peer Reviewed
• [Journal Article] Pathophysiological mechanisms of persistent orofacial pain (2020)
  • Author(s): Shinoda Masamichi、Hayashi Yoshinori、Kubo Asako、Iwata Koichi
  • Journal Title: Journal of Oral Science Volume: 62 Issue: 2 Pages: 131-135
  • DOI: 10.2334/josnusd.19-0373
  • NAID: 130007821522
  • ISSN: 1343-4934, 1880-4926
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Satellite Cell Activation via Nitric Oxide Signaling in Ectopic Orofacial Hypersensitivity (2020)
  • Author(s): Lee Jun、Ohara Kinuyo、Shinoda Masamichi、Hayashi Yoshinori、Kubo Asako、Sugawara Shiori、Asano Sayaka、Soma Kumi、Kanno Kohei、Ando Masatoshi、Koyama Ryo、Kimura Yuki、Sakanashi Kousuke、Iinuma Toshimitsu、Iwata Koichi
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 4 Pages: 1252-1252
  • DOI: 10.3390/ijms21041252
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suppression of superficial microglial activation by spinal cord stimulation attenuates neuropathic pain following sciatic nerve injury in rats. (2020)
  • Author(s): Shinoda M, Fujita S, Sugawara S, Asano S, Koyama R, Fujiwara S, Soma K, Tamagawa T, Matsui T, Ikutame D, Ando M, Osada A, Kimura Y, Kobayashi K, Yamamoto T, Kusama-Eguchi K, Kobayashi M, Hayashi Y, Iwata K.
  • Journal Title: International Journal of Molecular Sciences Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion. (2019)
  • Author(s): Matsuda T, Irie T, Katsurabayashi S, Hayashi Y, Nagai T, Hamazaki N, Adefuin AMD, Miura F, Ito T, Kimura H, Shirahige K, Takeda T, Iwasaki K, Imamura T, Nakashima K.
  • Journal Title: Neuron Volume: 101 (3) Issue: 3 Pages: 472-485
  • DOI: 10.1016/j.neuron.2018.12.010
  • Peer Reviewed / Open Access
• [Journal Article] Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis. (2019)
  • Author(s): Harada Y, Zhang J, Imari K, Yamasaki R, Ni J, Wu Z, Yamamoto K, Kira JI, Nakanishi H, Hayashi Y.
  • Journal Title: Pain Volume: 160 Issue: 9 Pages: 2050-2062
  • DOI: 10.1097/j.pain.0000000000001596
  • Peer Reviewed / Open Access
• [Journal Article] A TLR-CXCL1 pathway in DRG neurons induces neutrophil accumulation in the DRG and mechanical allodynia in EAE mice (2019)
  • Author(s): Zhang Jing、Harada Yuka、Hayashi Yoshinori
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12003-12003
  • DOI: 10.1038/s41598-019-48558-7
  • Peer Reviewed / Open Access
• [Journal Article] KCNMB3 in spinal microglia contributes to the generation and maintenance of neuropathic pain in mice (2019)
  • Author(s): Imari Kazuhisa、Harada Yuka、Zhang Jing、Mori Yoshihide、Hayashi Yoshinori
  • Journal Title: International Journal of Molecular Medicine Volume: - Pages: 1585-1593
  • DOI: 10.3892/ijmm.2019.4279
  • Peer Reviewed
• [Journal Article] Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain (2019)
  • Author(s): Sugawara Shiori、Shinoda Masamichi、Hayashi Yoshinori、Saito Hiroto、Asano Sayaka、Kubo Asako、Shibuta Ikuko、Furukawa Akihiko、Toyofuku Akira、Iwata Koichi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 24 Pages: 6360-6360
  • DOI: 10.3390/ijms20246360
  • Peer Reviewed / Open Access
• [Journal Article] Peripheral and Central Mechanisms of Persistent Orofacial Pain (2019)
  • Author(s): Shinoda Masamichi、Kubo Asako、Hayashi Yoshinori、Iwata Koichi
  • Journal Title: Frontiers in Neuroscience Volume: 13 Pages: 1-10
  • DOI: 10.3389/fnins.2019.01227
  • Peer Reviewed / Open Access
• [Journal Article] Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis. (2019)
  • Author(s): Harada Y, Zhang J, Imari K, Yamasaki R, Ni J, Wu Z, Yamamoto K, Kira JI, Nakanishi H, Hayashi Y
  • Journal Title: Pain Volume: .
  • Peer Reviewed / Open Access
• [Journal Article] Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion. (2019)
  • Author(s): Matsuda T, Irie T, Katsurabayashi S*, Hayashi Y*, Nagai T, Hamazaki N, Adefuin AMD, Miura F, Ito T, Kimura H, Shirahige K, Takeda T, Iwasaki K, Imamura T, Nakashima K
  • Journal Title: Neuron Volume: 101 Pages: 472-485
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. (2018)
  • Author(s): Ni J, Wu Z, Stoka V, Meng J, Hayashi Y, Peters C, Qing H, Turk V, Nakanishi H. Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice
  • Journal Title: Aging Cell Volume: . Issue: 1
  • DOI: 10.1111/acel.12856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain. (2018)
  • Author(s): Fujii T, Yamasaki R, Iinuma K, Tsuchimoto D, Hayashi Y, Saitoh BY, Matsushita T, Kido MA, Aishima S, Nakanishi H, Nakabeppu Y, Kira JI.
  • Journal Title: Annals of Neurology Volume: 84 Issue: 2 Pages: 208-224
  • DOI: 10.1002/ana.25279
  • Peer Reviewed / Open Access
• [Journal Article] Enantioselective Monoclonal Antibodies for Detecting Ketamine to Crack Down on Illicit Use (2018)
  • Author(s): Morita, I. Oyama, H. Kanda, Y. Yasuo, M. Ito, A. Toyota, M. Hayashi, Y. Yokoyama, T. Kobayashi, N.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 1 Pages: 123-131
  • DOI: 10.1248/bpb.b17-00762
  • NAID: 130006301299
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of cathepsin E interferes with neuronal differentiation of P19 embryonal teratocarcinoma cells by degradation of N-cadherin. (2017)
  • Author(s): Harada Y, Takayama F, Tanabe K, Ni J, Hayashu Y, Yamamoto K, Wu Z, Nakanishi H
  • Journal Title: 10.1007/s10571-016-0376-x. Volume: 37 Issue: 3 Pages: 437-443
  • DOI: 10.1007/s10571-016-0376-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An EP2 agonist facilitates NMDA-induced outward currents and inhibits dendritic beading through activation of BK channels in mouse cortical neurons. (2016)
  • Author(s): Hayashi Y, Morinaga S, Liu X, Zhang J, Wu Z, Yokoyama T, Nakanishi H
  • Journal Title: Mediators Inflamm Volume: 2016 Pages: 5079597-5079597
  • DOI: 10.1155/2016/5079597
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BK channels in microglia are required for (2016)
  • Author(s): Yoshinori Hayashi, Saori Morinaga, Jing Zhang, Yasushi Satoh, Andrea Meredith, Takahiro Nakata, Zhou Wu, Shinichi Kohsaka, Kazuhide Inoue, Hiroshi Nakanishi
  • Journal Title: Nature communications Volume: 7 Issue: 1 Pages: 11697-11697
  • DOI: 10.1038/ncomms11697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diurnal dynamic behavior of microglia in response to infected bacteria through the UDP-P2Y6 receptor system. (2016)
  • Author(s): Takayama F, Hayashi Y, Wu Z, Liu Y, Nakanishi H.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 30006-30006
  • DOI: 10.1038/srep30006
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ミクログリアのchannelopathyがもたらす痛みの慢性化機構の解明 基礎シンポジウム「知っておきたい痛みのメカニズム」 (2019)
  • Author(s): 林 良憲
  • Organizer: 第24回日本口腔顔面痛学会学術大会
  • Invited
• [Presentation] 好中球と神経の双方向性作用に基づいた痛みの発症メカニズム (2019)
  • Author(s): 林 良憲
  • Organizer: 次世代薬理学セミナー2019 in 那覇，日本薬理学会
  • Invited
• [Presentation] ミクログリアKCNMB3による神経障害性疼痛の制御 (2019)
  • Author(s): 今利一寿，石井広太郎，矢内雄太，大山順子，熊丸 渉，森 悦秀，林 良憲
  • Organizer: 第23回口腔顔面神経機能学会学術大会
• [Presentation] カテプシンE依存的に好中球で産生されるエラスターゼが実験的自己免疫性脳脊髄炎で生じる痛みに関与する (2019)
  • Author(s): 原田ゆか，中西 博，林 良憲
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 脊髄ミクログリアBKチャネルの神経障害性疼痛における役割 (2019)
  • Author(s): 佐藤 泰司，諸橋 徹，林 良憲，板倉 沙也子，川口 慎憲，中西 博，メレディス アンドレア，石塚 俊晶
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Neuroimmune interaction in the dorsal root ganglion induces mechanical allodynia in experimental autoimmune encephalomyelitis. (2019)
  • Author(s): Yoshinori Hayashi
  • Organizer: Neuro2019
• [Presentation] Neuroimmune interaction in the dorsal root ganglion induces mechanical allodynia in experimental autoimmune encephalomyelitis. (2019)
  • Author(s): Yoshinori Hayashi
  • Organizer: 内藤コンファレンス
  • Int'l Joint Research
• [Presentation] Direct conversion of microglia into neurons improves neurological recovery after ischemic injury. (2019)
  • Author(s): Takashi Irie, Taito Matsuda, Yoshinori Hayashi, Jun-ichi Kira, Kinichi Nakashima
  • Organizer: SfN Neuroscience2019
  • Int'l Joint Research
• [Presentation] ミクログリアのイオンチャネルの機能異常に基づいた神経障害性疼痛のメカニズム (2019)
  • Author(s): 林 良憲，篠田雅路，岩田幸一
  • Organizer: 第13回三叉神経領域の感覚-運動統合研究会
• [Presentation] マウスにおける神経幹細胞特異的ITPA欠損は神経細胞の脱分極を引き起こし，てんかん性発作と早期死亡の原因となる (2019)
  • Author(s): 土本 大介，古賀 祐一郎，林 良憲，アボルハッサニノナ，米嶋 康臣，作見 邦彦，中西 博，豊國 伸哉，中別府 雄作
  • Organizer: 第42回日本分子生物学会
• [Presentation] ミクログリアからニューロンへの直接分化転換による脳梗塞後の神経機能回復 (2019)
  • Author(s): 入江 剛史，松田 泰斗，林 良憲，吉良 潤一，中島 欽一
  • Organizer: 第42回日本分子生物学会
• [Presentation] Neuroimmune interaction in the dorsal root ganglion induces mechanical allodynia in experimental autoimmune encephalomyelitis (2019)
  • Author(s): Yoshinori Hayashi, Masamichi Shinoda, Koichi Iwata
  • Organizer: 8th Asian Pain Symposium
  • Int'l Joint Research
• [Presentation] カテプシンE依存的に好中球で産生されるエラスターゼが実験的自己免疫性脳脊髄炎で生じる痛みに関与する (2019)
  • Author(s): 原田ゆか、中西 博、林 良憲
  • Organizer: 第92回日本薬理学会
• [Presentation] 脊髄ミクログリアBKチャネルの神経障害性疼痛における役割 (2019)
  • Author(s): 佐藤 泰司、諸橋 徹、林 良憲、板倉 沙也子、川口 慎憲、中西 博、メレディス アンドレア、石塚 俊晶
  • Organizer: 第92回日本薬理学会
• [Presentation] 実験的自己免疫性脳脊髄炎におけるカテプシンEがもたらす免疫感覚異常 (2018)
  • Author(s): 林 良憲
  • Organizer: 第2回感覚免疫学研究会
  • Invited
• [Presentation] 実験的自己免疫性脳脊髄炎に伴う痛みはDRGに集積した好中球で発現誘導されるカテプシンEによって生じる (2018)
  • Author(s): 原田ゆか、中西 博、林 良憲
  • Organizer: 第40回日本疼痛学会
• [Presentation] Neural stem cell-specific Itpa knockout mouse as a model of human ITPA deficiency (2018)
  • Author(s): Tsuchimoto D, Koga Y, Hayashi Y, Abolhassani N, Yoneshima Y, Nakanishi H, Nakabeppu Y
  • Organizer: 第41回日本神経科学大会
• [Presentation] Neural stem cell-specific Itpa knockout mouse as a model of human epileptic encephalopathy caused by ITPA deficiency (2018)
  • Author(s): Tsuchimoto D, Koga Y, Hayashi Y, Abolhassani N, Yoneshima Y, Nakanishi H, Nakabeppu Y
  • Organizer: The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor International Symposium
• [Presentation] カテプシン依存的なプロテオリシスによる感覚情報の制御メカニズム (2017)
  • Author(s): 林 良憲
  • Organizer: 第40回日本神経科学大会
  • Invited
• [Presentation] 痛みの慢性化スイッチとしてのケラチノサイトの新たな役割 (2017)
  • Author(s): 林 良憲
  • Organizer: 第59回歯科基礎医学会学術大会
  • Invited
• [Presentation] カテプシンによる感覚情報の制御メカニズムの解明 (2017)
  • Author(s): 林 良憲
  • Organizer: 第39会日本疼痛学会
  • Invited
• [Presentation] ミクログリアBKチャネルを介したモルヒネ誘発性疼痛過敏の形成メカニズム (2016)
  • Author(s): 林 良憲、中西 博
  • Organizer: Japan Purine Club2016
  • Place of Presentation: 東京慈恵会医科大学
  • Year and Date: 2016-10-26