Elucidation of mitochondrial regulation and actin dynamics of umbilical cord-derived mesenchymal cells on microglia

• Project/Area Number: 20K22892
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Mukai Takeo 東京大学, 医学部附属病院, 助教 (60871324)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 臍帯由来間葉系細胞 / ミクログリア / アクチンダイナミクス / ミトコンドリア / 貪食能 / ＲｈｏＧＴＰａｓｅ / 間葉系細胞 / 臍帯

Outline of Research at the Start

本研究ではマウスのミクログリア初代培養活性化モデルと臍帯由来間葉系細胞（UC-MSC）の共培養を行うことで、活性化ミクログリアの形態変化と貪食能変化をアクチンダイナミクスの観点から共に追究し、そのメカニズムとなるミトコンドリア機能、細胞内cyclic AMP (cAMP) / cAMP-dependent protein kinase A (PKA)活性、PI3K / Akt - protein kinase C (PKC) pathwayの活性について検討することで、UC-MSCが活性化ミクログリアに及ぼすアクチンダイナミクスとそれによって生じる特性変化のメカニズムを解明する。

Outline of Final Research Achievements

We analyzed the changes in characteristics of umbilical cord-derived mesenchymal cells (UC-MSC) on LPS-activated microglial primary cultures. It was demonstrated that the inflammatory cytokine NFκB pathway of activated microglia was significantly reduced by UC-MSC, and that the reduced phagocytic ability and actin dynamics were improved by UC-MSC co-culture. We also demonstrated that cdc42 and Rac1 were significantly elevated in UC-MSC as the mechanism of these phenomena, which was contributed by the activation of the PI3K / Akt-Rho GTPase pathway. LPS stimulation did not significantly change the degree of mitochondrial depolarization.

Academic Significance and Societal Importance of the Research Achievements

UC-MSCが活性化ミクログリアに及ぼす形態変化・貪食能変化とそのメカニズムをアクチンダイナミクスの観点から解明した比較実験はなく、本研究が国内外初となる。従って本研究は損傷脳組織において活性型ミクログリアを鎮静化させる新規治療の基盤となり、将来のMSCを用いた細胞治療へと繋がる可能性を示すと考えられる。

Research Products

• [Journal Article] Umbilical cord-derived mesenchymal stromal cells immunomodulate and restore actin dynamics and phagocytosis of LPS-activated microglia via PI3K/Akt/Rho GTPase pathway. (2021)
  • Author(s): Takeo Mukai, Elena Di Martino, Shunichiro Tsuji, Klas Blomgren, Tokiko Nagamura-Inoue, Ulrika Aden
  • Journal Title: Cell death discovery Volume: 7 Issue: 1 Pages: 46-46
  • DOI: 10.1038/s41420-021-00436-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mesenchymal Stromal Cells Perspective: New Potential Therapeutic for the Treatment of Neurological Diseases (2021)
  • Author(s): Takeo Mukai, Kenshi Sei, Tokiko Nagamura-Inoue
  • Journal Title: Pharmaceutics Volume: 13 Issue: 8 Pages: 1159-1159
  • DOI: 10.3390/pharmaceutics13081159
  • Peer Reviewed / Open Access
• [Journal Article] Preventing Brain Damage from Hypoxic Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells (2021)
  • Author(s): Makoto Nabetani , Takeo Mukai, Haruo Shintaku
  • Journal Title: American Journal of Perinatology Volume: 5 Issue: 16 Pages: 5-5
  • DOI: 10.1055/s-0041-1726451
  • Peer Reviewed / Open Access
• [Journal Article] The Immunomodulatory Effect of Triptolide on Mesenchymal Stromal Cells (2021)
  • Author(s): Haiping He Atsuko Takahashi Takeo Mukai Akiko Hori Miwako Narita Arinobu Tojo Tonghua Yang Tokiko Nagamura-Inoue
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 12-12
  • DOI: 10.3389/fimmu.2021.686356
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 臍帯由来間葉系細胞が活性化型ミクログリアに及ぼす特性変化についての検討 (2021)
  • Author(s): 向井丈雄
  • Organizer: 第20回日本再生医療学会総会