Therapeutic gene transfer enhances neuroprotective effects of dental pulp stem cells following focal cerebral ischemia ~ for clinical application ~

• Project/Area Number: 18K08981
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Nippon Medical School
• Principal Investigator: Chikako Nito 日本医科大学, 医学部, 教授 (30409172)
• Co-Investigator(Kenkyū-buntansha): 須田 智 日本医科大学, 医学部, 准教授 (00366733)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 幹細胞治療 / 歯髄幹細胞 / AAVベクター / 脳保護効果 / 脳梗塞 / 歯髄由来間葉系幹細胞 / 炎症抑制 / 血管新生 / 血液脳関門障害 / 脳虚血モデル / アデノ随伴ウイルスベクター / 肝細胞増殖因子 / 血液脳関門 / 遺伝子治療 / 幹細胞移植 / 脳虚血 / 局所脳虚血モデル / 神経細胞保護

Outline of Final Research Achievements

Administration of DPSCs (DPSC/HGF), in which hepatocyte growth factor (HGF) as a therapeutic gene was strongly expressed, to an acute ischemic stroke model showed a more significant infarct reduction than administration of DPSCs alone, and also showed significant improvement in the motor function of the animals. The mechanism of these effects was thought to be the suppression of neuronal cell death due to anti-inflammatory effects, the reduction of blood-brain barrier damage and the promotion of angiogenesis. Furthermore, tracing of the transplanted cells showed that no cell viability was observed in the ischaemic brain haemisphere after 14 days of reperfusion, suggesting that the transplanted DPSCs/HGF did not survive in the brain for a long time, and that the enhancement of HGF expression in the host was transient and caused few side effects such as immunosuppression.

Academic Significance and Societal Importance of the Research Achievements

この研究成果は、遺伝子修飾を施した治療用細胞を損傷脳組織に導入し、適切な期間維持させる方法を開発する基盤となり、新規脳梗塞治療へとつながる可能性がある。

Research Products

• [Journal Article] Dental-Pulp Stem Cells as a Therapeutic Strategy for Ischemic Stroke (2022)
  • Author(s): Nito Chikako、Suda Satoshi、Nitahara-Kasahara Yuko、Okada Takashi、Kimura Kazumi
  • Journal Title: Biomedicines Volume: 10 Issue: 4 Pages: 737-737
  • DOI: 10.3390/biomedicines10040737
  • Peer Reviewed / Open Access
• [Presentation] Transplantation of human dental pulp stem cells attenuates brain injury after transient middle cerebral artery occlusion. (2019)
  • Author(s): Nito C, Sowa K, Sakamoto Y, Takahashi S, Arakawa M, Suda S, Nishiyama Y, Takahashi A N, Kasahara YN, Kimura K, Okada T.
  • Organizer: 第25回 日本遺伝子細胞治療学会学術集会
• [Presentation] Neuroprotective effects of human dental pulp stem cells after acute cerebral ischemia. (2019)
  • Author(s): Nito C, Suda S, Sowa K, Nakajima M, Sakamoto Y, Takahashi S, Nishiyama Y, Kasahara YN, Okada T, Kimura K.
  • Organizer: The 25th Internal Symposium on Cerebral Blood Flow, Metabolism, and Function
  • Int'l Joint Research