underlying mechanisms of cell therapy using tissue protective-peripheral blood mononuclear cells against ischemic stroke

• Project/Area Number: 20K16485
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Niigata University
• Principal Investigator: Hatakeyama Masahiro 新潟大学, 脳研究所, 助教 (20843618)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 再生医療 / 細胞療法 / 脳虚血 / 末梢血単核球 / 低酸素領域 / 機能再生 / 低酸素低糖刺激 / 脳梗塞 / 再生医学

Outline of Research at the Start

脳梗塞後，低酸素低糖刺激をした末梢血単核球を投与すると，脳梗塞巣での血管新生・神経再生が亢進し，脳梗塞後遺症が改善することをこれまで示してきた．しかし，細胞投与後の血管新生・神経再生がどのような機序で生じるのかは不明であった．本研究では，細胞投与後の脳内での組織修復因子の局在，ならびに血管新生が神経再生に及ぼす影響を，組織学的に検討することにより，上記の機序の解明を目指す．

Outline of Final Research Achievements

We demonstrated that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD) to rats with a cerebral ischemia model significantly increased VEGF expression in microglia within the rat brain at 21 days post-administration compared to the control group. This difference was not observed in neurons or vascular endothelial cells. Similarly, we found that TGF-β expression in microglia was increased in the OGD-PBMC administered group.
Furthermore, histological analysis revealed that OGD-PBMCs migrate to hypoxic regions after ischemia-reperfusion and exert therapeutic effects.

Academic Significance and Societal Importance of the Research Achievements

OGD-PBMCを用いた細胞療法は，従来の細胞療法に比し，安全かつ低コストな脳梗塞治療を実現しうるものと期待できる．現在，当研究室では同技術の臨床応用を目指した研究を進めている．本研究では，同技術の作用機序の一部を明らかにすることにより，臨床応用実現に一歩近づくことができたと考える．

Research Products

• [Journal Article] Next-generation regenerative therapy for ischemic stroke using peripheral blood mononuclear cells (2024)
  • Author(s): Kanazawa Masato、Ninomiya Itaru、Otsu Yutaka、Hatakeyama Masahiro
  • Journal Title: Neural Regeneration Research Volume: 19 Issue: 11 Pages: 2341-2342
  • DOI: 10.4103/nrr.nrr-d-23-01784
  • Peer Reviewed / Open Access
• [Journal Article] Oxygen?Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke (2023)
  • Author(s): Otsu Yutaka、Hatakeyama Masahiro、Kanayama Takeshi、Akiyama Natsuki、Ninomiya Itaru、Omae Kaoru、Kato Taisuke、Onodera Osamu、Fukushima Masanori、Shimohata Takayoshi、Kanazawa Masato
  • Journal Title: Neurotherapeutics Volume: 20 Issue: 5 Pages: 1369-1387
  • DOI: 10.1007/s13311-023-01398-w
  • Peer Reviewed / Open Access
• [Presentation] Oxygen-glucose deprived peripheral blood mononuclear cells alter microglial phenotype by secretome (2024)
  • Author(s): Masahiro Hatakeyama, Yutaka Otsu, Natsuki Akiyama, Takeshi Kanayama, Itaru Ninomiya, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa
  • Organizer: 第65回日本神経学会学術大会
• [Presentation] Peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation regulate microglial polarization by secretome after cerebral ischemia (2024)
  • Author(s): Masahiro Hatakeyama, Yutaka Otsu, Natsuki Akiyama, Takeshi Kanayama, Itaru Ninomiya, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa
  • Organizer: International Stroke Conference 2024
  • Int'l Joint Research
• [Presentation] Peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation cause microglial phenotype conversion by secretome after cerebral ischemia (2023)
  • Author(s): Masahiro Hatakeyama, Yutaka Otsu, Natsuki Akiyama, Takeshi Kanayama, Itaru Ninomiya, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa
  • Organizer: 11th Japan-Korea Joint Stroke Conference
  • Int'l Joint Research
• [Presentation] 脳梗塞に対する低酸素低糖刺激末梢血単核球投与による脳内変化 (2022)
  • Author(s): 金山武史，畠山公大，大津裕，秋山 夏葵，二宮格，小野寺理，下畑享良 ，金澤雅人
  • Organizer: 第65回日本脳循環代謝学会学術集会