The elucidation of therapeutic effect on neural regeneration by neural cell transplantation

• Project/Area Number: 19K20681
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 90110:Biomedical engineering-related
• Research Institution: Kansai Medical University
• Principal Investigator: MURAYAMA Masanori 関西医科大学, 医学部, 講師 (60737675)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルツハイマー型認知症 / 疾患モデル / 神経細胞 / 再生医療 / 精神神経症状 / 疾患モデルマウス / ヒトiPS細胞 / 雌雄差 / 認知症 / iPS細胞 / 神経細胞移植 / 認知機能 / 神経精神状況 / 神経回路

Outline of Research at the Start

アルツハイマー型認知症は神経細胞の損傷により認知機能だけでなく神経精神症状に異常が生じることが知られている。これまでの研究成果から、神経細胞移植により認知機能が改善することを見出しているが、神経回路の再構築や神経精神状況に対する影響は明らかではない。そこで、本研究計画では神経細胞トレーサーを用いて神経回路の再構築における神経細胞移植の役割を評価すると共に、神経精神状況に対する神経細胞移植の治療効果を検討する。

Outline of Final Research Achievements

Alzheimer's disease (AD) is one of neurodegenerative disorders. The degree of neural cell loss in hippocampus correlates with the severity of AD. Cognitive dysfunction and neuropsychiatric symptoms (NPS), such as anxiety and depression, are typical features of AD.
We found that neural cell transplantation into dentate gyrus in hippocampus improved cognitive dysfunction and also NPS (anxiety and depression) in AD model mice. A correlation analysis revealed that the spatial learning function of AD model mice was correlated with their NPS scores both before and after neural cell transplantation in a similar manner. In contrast, in the AD model mice subjected to neural cell transplantation, spatial reference memory function was not correlated with NPS scores. These results suggested the neural cell transplantation in the AD model mice significantly improved NPS to the same degree as cognitive dysfunctions, possibly via distinct mechanisms, such as the cholinergic and GABAergic systems.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー型認知症は加齢と共に患者数が増加する神経変性疾患であり、超高齢化社会である日本では解決すべき課題であるが、根治療法は確立されていない。再生医療技術による治療が期待されるが、認知機能だけでなくBPSDに着目した報告はわずかである。本研究では神経細胞移植が認知機能に加えBPSDを改善することを明らかにしており、臨床応用への重要な知見となる。

Research Products

• [Journal Article] Nicotine treatment regulates PD-L1 and PD-L2 expression via inhibition of Akt pathway in HER2-type breast cancer cells (2022)
  • Author(s): Murayama Masanori A.、Takada Erika、Takai Kenji、Arimitsu Nagisa、Shimizu Jun、Suzuki Tomoko、Suzuki Noboru
  • Journal Title: PLOS ONE Volume: 17 Issue: 1 Pages: e0260838-e0260838
  • DOI: 10.1371/journal.pone.0260838
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nicotine treatment shows the therapeutic effect for imiquimod-induced psoriasiform dermatitis in alpha 7-nicotinic acetylcholine (2022)
  • Author(s): Murayama Masanori A
  • Journal Title: Translat Regulat Sci Volume: In Press
  • Peer Reviewed / Open Access
• [Journal Article] Dementia model mice exhibited improvements of neuropsychiatric symptoms as well as cognitive dysfunction with neural cell transplantation (2021)
  • Author(s): Murayama Masanori A.、Arimitsu Nagisa、Shimizu Jun、Fujiwara Naruyoshi、Takai Kenji、Okada Yoko、Hirotsu Chieko、Takada Erika、Suzuki Tomoko、Suzuki Noboru
  • Journal Title: Experimental Animals Volume: 70 Issue: 3 Pages: 387-397
  • DOI: 10.1538/expanim.21-0008
  • NAID: 130008072160
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Female dominance of both spatial cognitive dysfunction and neuropsychiatric symptoms in a mouse model of Alzheimer’s disease (2021)
  • Author(s): Murayama Masanori A.、Arimitsu Nagisa、Shimizu Jun、Fujiwara Naruyoshi、Takai Kenji、Ikeda Yoshiki、Okada Yoko、Hirotsu Chieko、Takada Erika、Suzuki Tomoko、Suzuki Noboru
  • Journal Title: Experimental Animals Volume: 70 Issue: 3 Pages: 398-405
  • DOI: 10.1538/expanim.21-0009
  • NAID: 130008072161
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation (2021)
  • Author(s): Murayama Masanori A.、Chi Hsi-Hua、Matsuoka Mako、Ono Takahiro、Iwakura Yoichiro
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 607346-607346
  • DOI: 10.3389/fimmu.2021.607346
  • Peer Reviewed / Open Access
• [Journal Article] The importance of neuropsychiatric symptom in Alzheimer's disease (2021)
  • Author(s): Murayama Masanori A.
  • Journal Title: Precision Medicine Volume: 4(5) Pages: 467-469
  • NAID: 40022590481
  • Peer Reviewed
• [Journal Article] The experimental model mice to understanding of rheumatoid arthritis: a brief review (2021)
  • Author(s): Murayama Masanori A.
  • Journal Title: The Allergy in Practice Volume: 41(6) Pages: 533-535
  • Peer Reviewed
• [Journal Article] Relationship between skewed T cell differentiation and gut microbiota alternation in human immunological disorders. Secondary publication (2021)
  • Author(s): Shimizu Jun、Murayama Masanori A.、Suzuki Noboru
  • Journal Title: The Allergy in Practice Volume: 41(7) Pages: 618-622
  • Peer Reviewed
• [Journal Article] The experimental models for osteoarthritis (2021)
  • Author(s): Murayama Masanori A.
  • Journal Title: Precision Medicine Volume: 4(9) Pages: 896-898
  • NAID: 40022670889
  • Peer Reviewed
• [Journal Article] The experimental models for psoriasiform dermatitis (2021)
  • Author(s): Murayama Masanori A.
  • Journal Title: The Allergy in Practice Volume: 41(10) Pages: 889-891
  • Peer Reviewed
• [Journal Article] The therapeutic effect of iPS cells-derived neural cell transplantation into dementia model mice (2021)
  • Author(s): Murayama Masanori A.
  • Journal Title: The CELL Volume: 53(11) Pages: 710-711
  • Peer Reviewed
• [Journal Article] The regenerative medicine for Alzheimer's disease, focused on neuropsychiatric symptom (2021)
  • Author(s): Murayama Masanori A.
  • Journal Title: Bessatsu BIO Clinica Volume: 10(2) Pages: 119-122
  • Peer Reviewed
• [Journal Article] Immunopathology in multiple sclerosis and experimental models (2021)
  • Author(s): Arimitsu N、Murayama Masanori A.
  • Journal Title: The Allergy in Practice Volume: 41(13) Pages: 1208-1211
  • Peer Reviewed
• [Journal Article] Relationship between skewed T cell differentiation and gut microbiota alternation in human immunological disorders. Secondary publication (2021)
  • Author(s): Shimizu Jun、Murayama Masanori A.、Suzuki Noboru
  • Journal Title: Precision Medicine Volume: 4(14) Pages: 1379-1383
  • Peer Reviewed
• [Journal Article] TARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens (2021)
  • Author(s): Yabe Rikio、Chung Soo-Hyun、Murayama Masanori A.、Kubo Sachiko、Shimizu Kenji、Akahori Yukiko、Maruhashi Takumi、Seno Akimasa、Kaifu Tomonori、Saijo Shinobu、Iwakura Yoichiro
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 94-94
  • DOI: 10.1038/s41467-020-20307-9
  • Peer Reviewed / Open Access
• [Journal Article] The next therapeutic target in osteoarthritis: CTRP3 (2021)
  • Author(s): MURAYAMA Masanori A.
  • Journal Title: The Allergy in Practice Volume: 41 Pages: 225-228
  • Peer Reviewed
• [Journal Article] C1q/TNF-related protein 3 regulates chondrogenic cell proliferation via adiponectin receptor 2 (progestin and adipoQ receptor 2) (2020)
  • Author(s): MURAYAMA Masanori A.、IWAKURA Yoichiro
  • Journal Title: Translational and Regulatory Sciences Volume: 2 Issue: 1 Pages: 19-23
  • DOI: 10.33611/trs.2_19
  • NAID: 130007814846
  • ISSN: 2434-4974
  • Peer Reviewed / Open Access
• [Journal Article] The relationship between cognitive functions and neuropsychiatric symptoms in Alzheimer’s disease (2020)
  • Author(s): MURAYAMA Masanori A.
  • Journal Title: BIO Clinica Volume: 35 Pages: 377-379
  • Peer Reviewed
• [Journal Article] The development of Alzheimer's disease models (2020)
  • Author(s): MURAYAMA Masanori A.
  • Journal Title: BIO Clinica Volume: 35 Pages: 975-977
  • Peer Reviewed
• [Journal Article] The relationship between cognitive functions and neuropsychiatric symptoms in Alzheimer’s disease. (2020)
  • Author(s): Murayama MA.
  • Journal Title: BIO Clinica Volume: 35(4) Pages: 377-379
• [Journal Article] Transplantation of Human iPS Cell-Derived Neural Cells with an Artificial Nerve Conduit Leads to Cellular Retention in the Transplanted Area and Improves Motor Function in a Mouse Spinal Cord Injury Model (2019)
  • Author(s): Tomochika K, Arimitsu N, Murayama MA, Hirotsu C, Nagata K, Takai K, Shimizu J, Akazawa T, Torii Y, Umehara T, Iinuma M, Niki H, Suzuki N.
  • Journal Title: Journal of St. Marianna University Volume: 10 Issue: 2 Pages: 27-37
  • DOI: 10.17264/stmarieng.10.27
  • NAID: 130007791218
  • ISSN: 2185-1336, 2189-0277
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between skewed T cell differentiation and gut microbiota alternation in human immunological disorders. (2019)
  • Author(s): Shimizu J, Murayama MA, Suzuki N.
  • Journal Title: Agricultural Biotechnology. Volume: 3(13) Pages: 1260-1264
• [Journal Article] Complement system as a therapeutic target for osteoarthritis. (2019)
  • Author(s): Murayama MA.
  • Journal Title: Precision Medicine Volume: 2(11) Pages: 1086-1087
• [Journal Article] The pathogenic role of the complement activation in the development of osteoarthritis. (2019)
  • Author(s): Murayama MA.
  • Journal Title: BIO Clinica Volume: 34(8) Pages: 852-853
• [Journal Article] Relationship between skewed T cell differentiation and gut microbiota alternation in human immunological disorders. (2019)
  • Author(s): Shimizu J, Murayama MA, Suzuki N.
  • Journal Title: The Allergy in Practice Volume: 38(7) Pages: 599-603
• [Journal Article] Roles of Reelin/Disabled1 pathway on functional recovery of hemiplegic mice after neural cell transplantation; Reelin promotes migration toward motor cortex and maturation to motoneurons of neural grafts. (2019)
  • Author(s): Arimitsu N, Takai K, Fujiwara N, Shimizu J, Ueda Y, Wakisaka S, Hirotsu C, Murayama M A, Suzuki T, Suzuki N
  • Journal Title: Exp Neurol Volume: 320 Pages: 112970-112970
  • DOI: 10.1016/j.expneurol.2019.112970
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between skewed T cell differentiation and gut microbiota alternation in human immunological disorders. (2019)
  • Author(s): Shimizu J, Murayama MA, Suzuki N.
  • Journal Title: Precision Medicine Volume: 2(4) Pages: 364-368
• [Journal Article] The therapeutic approach to the pathogenesis of osteoarthritis. (2019)
  • Author(s): Murayama MA.
  • Journal Title: Bessatu BIO Clinica Volume: 7(2) Pages: 100-102
• [Presentation] 疾患モデルを用いた免疫疾患発症機構の解明 (2021)
  • Author(s): 村山正承
  • Organizer: 関西医科大学 私立大学研究ブランディング事業シンポジウム
• [Presentation] 腫瘍免疫での免疫チェックポイントに対するニコチンの影響 (2021)
  • Author(s): 鈴木登, 村山正承, 高田えりか, 高井憲治, 有光なぎさ, 廣津千恵子
  • Organizer: 喫煙科学研究財団令和２年度研究発表会
• [Presentation] 免疫システム完全ヒト化モデル動物の開発及び応用を目指した基礎研究 (2021)
  • Author(s): 村山正承, 徳弘圭造, 福田尚代, 上岡祐治, 植田祥啓, 岩井大, 神田晃, 埜中正博, 岩田亮一, 林美樹夫
  • Organizer: 第5回関西医科大学学術祭
• [Presentation] 変形性関節症の治療法開発を目指した、軟骨細胞増殖制御機構の解明 (2021)
  • Author(s): 村山正承
  • Organizer: 第5回関西医科大学学術祭
• [Presentation] 変形性関節症におけるCTRP6の役割の解析 (2020)
  • Author(s): 村山正承, 紀熙華, 岩倉洋一郎.
  • Organizer: 第67回日本実験動物学会総会
• [Presentation] インテグリン関連疾患治療薬開発に向けた薬剤スクリーニング法の開発. (2019)
  • Author(s): Ikeda Y, Kondo N, Takeda H, Makita Y, Fukunishi Y, Ueda Y, Sato K, Murayama M, Ma B, Isaka Y, Kawai K, Mashimo T, Kamioka Y, Araki M, Omote M, Kinasi T.
  • Organizer: 第10回スクリーニング学研究会
• [Presentation] The therapeutic effect of neural transplantation for Alzheimer’s disease. (2019)
  • Author(s): Murayama MA.
  • Organizer: 2019 Retreat of Advances in Animal Models of Disease & Translational Research.
  • Invited
• [Presentation] 完全離断精髄損傷マウスモデルに対する神経再生誘導チューブ併用ヒトiPS細胞由来神経幹/前駆細胞移植の検討. (2019)
  • Author(s): 友近顕, 有光なぎさ, 廣津千恵子, 高井憲治, 村山正承, 赤澤努, 梅原亮, 飯沼雅央, 清水潤, 仁木久照, 鈴木登.
  • Organizer: 第34回日本整形外科学会基礎学術集会.
• [Presentation] 生物に普遍的に存在する分泌型リボヌクレアーゼ遺伝子欠損マウスの表現型解析. (2019)
  • Author(s): 王辰, 角田茂, 小川哲弘, 岩本京夏, 餅井眞太郎, Desamero Mark Joseph, 藤井渉, チェンバーズ ジェームズ, 内田萌菜, 村山正承, 小川修平, 米澤智洋, 中山裕之, 岩倉洋一郎, 久和茂.
  • Organizer: 第84回日本インターフェロン・サイトカイン学会学術集会
• [Presentation] Elucidating the role of CTRP6 in renal fibrosis and acute kidney failure. (2019)
  • Author(s): Chi HH, Murayama M, Iwakura Y.
  • Organizer: 第84回日本インターフェロン・サイトカイン学会学術集会
• [Presentation] 腫瘍免疫での免疫チェックポイントに対するニコチンの影響. (2019)
  • Author(s): 鈴木登, 村山正承, 有光なぎさ, 高井憲治, 清水潤, 高田えりか, 廣津千恵子.
  • Organizer: 喫煙科学研究財団平成30年度助成研究発表会
• [Presentation] 普遍的リボヌクレアーゼのin vivo機能解析. (2019)
  • Author(s): 角田茂, 小川哲弘, 藤井渉, チェンバーズ ジェームズ, 王辰, 餅井眞太郎, Mark Joseph Desamero, 岩本京夏, 内田萌菜, 村山正承, 小川修平, 米澤智洋, 中山祐之, 岩倉洋一郎, 久和茂.
  • Organizer: 第9回オルソオルガノジェネシス検討会
• [Presentation] 認知症モデルマウスを用いたヒトiPS細胞由来神経細胞移植による認知機能改善における心理症状の評価と関連 (2019)
  • Author(s): 村山正承, 藤原成芳, 高井憲治, 清水潤, 鈴木登.
  • Organizer: 第66回日本実験動物学会総会
• [Remarks] TARM1が関節リウマチ治療に対する新たな治療標的となる可能性ー東京理科大ほか
  • URL: http://www.qlifepro.com/news/20210323/tarm1.html
• [Remarks] BioJapan, CTRP6およびCTRP3を用いた自己免疫および骨代謝疾患の治療
  • URL: https://biojapan2021.jcdbizmatch.jp/jp/Presentation/Info/Exhibitor?param=LFgd6uvX1EM
• [Remarks] 東京理科大学生命医科学研究所実験動物学研究部門HP
  • URL: https://www.rs.tus.ac.jp/iwakuralab/pdf/20211202.pdf
• [Remarks] 東京理科大学生命医科学研究所HP
  • URL: https://www.ribs.tus.ac.jp/index.php/2021/12/02/2377/
• [Remarks] 関西医科大学プレスリリース, 自己免疫疾患に対する新たな治療標的の発見
  • URL: https://www.kmu.ac.jp/news/laaes7000000iv6z-att/20211203Press_Release.pdf
• [Remarks] CTRP3は受容体AdipoR2(PAQR2)を介して軟骨細胞増殖を制御する
  • URL: https://www.rs.tus.ac.jp/iwakuralab/pdf/Murayama%20TRS2020.pdf
• [Remarks] ヒト疾患モデル動物の作製支援
  • URL: http://www.kmu.ac.jp/research/branding/paper/laaes7000000bfmq-att/07Modeldoubutsu.pdf
• [Remarks] 関節リウマチに対する新たな治療標的分子の候補を発見
  • URL: https://www.tus.ac.jp/mediarelations/archive/20210317_1224.html
• [Patent(Industrial Property Rights)] Th17細胞誘導性疾患の予防又は治療剤、及びTh17細胞誘導性疾患の予防又は、治療剤のスクリーニング方法. (2019)
  • Inventor(s): 岩倉洋一郎, 村山正承, 小野貴裕, 松岡眞子.
  • Industrial Property Rights Holder: 岩倉洋一郎, 村山正承, 小野貴裕, 松岡眞子.
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019