Development of curative therapies for demyelinating diseases utilizing exosomes from vascular endothelial cells

• Project/Area Number: 18H02522
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Gunma University
• Principal Investigator: ISHIZAKI YASUKI 群馬大学, 大学院医学系研究科, 教授 (90183003)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 血管内皮細胞 / 白質梗塞 / エクソソーム / 移植 / オリゴデンドロサイト / ミエリン / 制御性T細胞 / 内皮細胞 / 脱髄疾患 / 再髄鞘化 / iPS細胞 / 再生医療

Outline of Final Research Achievements

We found PDGF-B localized on the outer surface of the exosomes from cerebral microvascular endothelial cells (MVECs) promotes proliferation of oligodendrocyte precursor cells (OPCs). This result strongly suggests that the beneficial effect of MVEC transplantation on white matter infarct is mediated by PDGF signaling.
We also found that transplantation of vascular endothelial cells generated from human iPS cells (iVECs) increased the number of OPCs, reduced inflammation, and greatly enhanced remyelination of demyelinated axons in white matter infarct.

Academic Significance and Societal Importance of the Research Achievements

中高年初発うつ病では、MRI画像上、深部白質の高信号がしばしば認められ、脱髄変化を反映していると考えられている。大脳白質病変は他に認知障害や歩行障害などとも関連性が示されている。また大脳白質病変は経過とともに進行する例が多く、改善することはないとされている。この脱髄変化に対して有効な治療法が開発されれば、中高年初発うつ病、認知障害、歩行障害の予防法や治療法の開発に繋がる可能性が考えられる。
本研究により得られた成果は白質梗塞等の脱髄疾患一般の治療戦略開発の基盤となる知見であると考える。

Research Products

• [Journal Article] Transplantation of iPS‐derived vascular endothelial cells improves white matter ischemic damage (2020)
  • Author(s): Xu Bin、Kurachi Masashi、Shimauchi‐Ohtaki Hiroya、Yoshimoto Yuhei、Ishizaki Yasuki
  • Journal Title: Journal of Neurochemistry Volume: － Issue: 6 Pages: 759-771
  • DOI: 10.1111/jnc.14949
  • Peer Reviewed / Open Access
• [Journal Article] TRPC5 regulates axonal outgrowth in developing retinal ganglion cells. (2020)
  • Author(s): Oda M, Yamamoto H, Matsumoto H, Ishizaki Y, *Shibasaki K
  • Journal Title: Lab. Invest. Volume: 100 Issue: 2 Pages: 297-310
  • DOI: 10.1038/s41374-019-0347-1
  • Peer Reviewed
• [Journal Article] Deletion of Class II ADP-Ribosylation Factors in Mice Causes Tremor by the Nav1.6 Loss in Cerebellar Purkinje Cell Axon Initial Segments. (2019)
  • Author(s): Hosoi N, Shibasaki K, Hosono M, Konno A, Shinoda Y, Kiyonari H, Inoue K, Muramatsu SI, Ishizaki Y, Hirai H, Furuichi T, Sadakata T
  • Journal Title: J Neurosci Volume: 39(32) Issue: 32 Pages: 6339-6353
  • DOI: 10.1523/jneurosci.2002-18.2019
  • Peer Reviewed
• [Journal Article] Temperature elevation in epileptogenic foci exacerbates epileptic discharge through TRPV4 activation (2019)
  • Author(s): Shibasaki Koji、Yamada Katsuya、Miwa Hideki、Yanagawa Yuchio、Suzuki Michiyasu、Tominaga Makoto、Ishizaki Yasuki
  • Journal Title: Laboratory Investigation Volume: 100 Issue: 2 Pages: 274-284
  • DOI: 10.1038/s41374-019-0335-5
  • Peer Reviewed
• [Journal Article] The dynamics of revascularization after white matter infarction monitored in Flt1-tdsRed and Flk1-GFP mice (2019)
  • Author(s): Shimauchi-Ohtaki Hiroya、Kurachi Masashi、Naruse Masae、Shibasaki Koji、Sugio Shouta、Matsumoto Ken、Ema Masatsugu、Yoshimoto Yuhei、Ishizaki Yasuki
  • Journal Title: Neuroscience Letters Volume: 692 Pages: 70-76
  • DOI: 10.1016/j.neulet.2018.10.057
  • Peer Reviewed / Open Access
• [Journal Article] BMP4 signaling in NPCs upregulates Bcl-xL to promote their survival in the presence of FGF-2 (2018)
  • Author(s): Yamamoto Hanako、Kurachi Masashi、Naruse Masae、Shibasaki Koji、Ishizaki Yasuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 496 Issue: 2 Pages: 588-593
  • DOI: 10.1016/j.bbrc.2018.01.090
  • Peer Reviewed
• [Presentation] 脳微小血管内皮細胞由来の細胞外小胞の表面に存在するPDGF-Bはオリゴデンドロサイト前駆細胞の増殖を促進する (2020)
  • Author(s): 倉知正、徐彬、大澤祥、松崎利行、好本裕平、石崎泰樹
  • Organizer: 第63回日本神経化学会大会
• [Presentation] Transplantation of iPS-derived vascular endothelial cells ameliorates white matter infarct (2020)
  • Author(s): Xu Bin, Kurachi Masashi, Shimauchi-Ohtaki Hiroya, Yoshimoto Yuhei, Ishizaki Yasuki
  • Organizer: The 10th Conference of International Society of Radiation Neurobiology
• [Presentation] The dynamics of revascularization after white matter infarction monitored in Flt1-tdsRed and Flk1-GFP mice. (2019)
  • Author(s): Shimauchi-Otaki Hiroya, Kurachi Masashi, Naruse Masae, Shibasaki Koji, Sugio Shouta, Matsumoto Ken, Ema Masatsugu, Yoshimoto Yuhei, Ishizaki Yasuki
  • Organizer: The 29th International Symposium on Cerebral Blood Flow, Metabolism and Function
  • Int'l Joint Research
• [Presentation] A role for PDGF-B in the stimulatory effect of exosomes from cerebral microvascular endothelial cells on proliferation of oligodendrocyte precursor cells. (2019)
  • Author(s): Ishizaki Yasuki, Kurachi Masashi, Xu Bin, Matsuzaki Toshiyuki
  • Organizer: The 14th European Meeting on Glial Cells in Health and Disease
  • Int'l Joint Research
• [Presentation] Calpain/calpastatin system plays a role for control of NPC survival via cleavage of Bax. (2019)
  • Author(s): Yamamoto Hanako, Kurachi Masashi, Shibasaki Koji, Naruse Masae, Ishizaki Yasuki
  • Organizer: Neuro 2019（第42回日本神経科学大会・第62回日本神経化学会大会）
• [Presentation] PDGF-B in the extracellular vesicles from brain microvascular endothelial cells promotes proliferation of oligodendrocyte precursor cells. (2019)
  • Author(s): Kurachi Masashi, Xu Bin, Osawa Sho, Matsuzaki Toshiyuki, Ishizaki Yasuki
  • Organizer: Neuro 2019（第42回日本神経科学大会・第62回日本神経化学会大会）
• [Presentation] Effect of transplantation of iPS-derived vascular endothelial cells on white matter infarct. (2019)
  • Author(s): Xu Bin, Kurachi Masashi, Shimauchi-Ohtaki Hiroya, Yoshimoto Yuhei, Ishizaki Yasuki
  • Organizer: 第92回日本生化学会大会
• [Presentation] 局所脱髄によって活性化されたミクログリアは脳室下層よりOPC産生を誘導する (2018)
  • Author(s): 成瀬雅衣 柴崎貢志 島内寛也 石崎泰樹
  • Organizer: 第41回日本神経科学大会
• [Presentation] A role for Bax in control of NPC apoptosis by combined FGF2 and BMP4 signaling (2018)
  • Author(s): 山本華子 倉知正 成瀬雅衣 柴崎貢志 石崎泰樹
  • Organizer: 第91回日本生化学会大会