Inhibiting Scar Development for Promoting Stem Cell Engraftment in Chronic Spinal Cord Injuries.

• Project/Area Number: 16K21360
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery; Neurochemistry/Neuropharmacology
• Research Institution: Keio University
• Principal Investigator: Renault-Mihara Francois 慶應義塾大学, 医学部(信濃町), 特任講師 (20570427)
• Research Collaborator: SON Iki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Spinal cord injury / reactive astrocytes / glial scar / chronic scar / stem cell / STAT3 / RhoA / astrocytes / spinal cord injury / stat3 / gene regulation / 脊椎脊髄病学 / 幹細胞生物学 / 再生 / 修復

Outline of Final Research Achievements

#1: We found that molecule X, regulates the expression of several proteases and induces lesion remodeling after SCI, but the survival rate and distribution of transplanted neural stem cells are unchanged, which led us to abandon the theme. #2 The characterization of the gene expression profile of scar-forming reactive astrocytes has been reported by another research group (Hara M. et al., Nature Medicine, 2017). #3: We found that the transcription factor STAT3 regulates the dynamics of reactive astrocytes in vitro and glial scar formation in vivo. This study was published in the Journal of Cell Biology (Renault-Mihara et al., 2017).#4: Two different experimental models were used to characterize novel markers of pathological nerve scars. Our hypothesis is those genes are associated with incomplete healing in the central nervous system. This study is still in progress.

Academic Significance and Societal Importance of the Research Achievements

Spinal cord injury is a major medical problem as all the surviving patients inevitably become chronic patients. Our research focusing on the mechanisms of scar formation and stabilization in the subacute and chronic phases respectively may help design new therapeutic strategies.

Research Products

• [Journal Article] Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury (2019)
  • Author(s): Kojima Kota、Miyoshi Hiroyuki、Nagoshi Narihito、Kohyama Jun、Itakura Go、Kawabata Soya、Ozaki Masahiro、Iida Tsuyoshi、Sugai Keiko、Ito Shuhei、Fukuzawa Ryuji、Yasutake Kaori、Renault-Mihara Francois、Shibata Shinsuke、Matsumoto Morio、Nakamura Masaya、Okano Hideyuki
  • Journal Title: Stem Cells Transl Med Volume: 8 Pages: 260-270
  • DOI: 10.1002/sctm.18-0096
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations (2018)
  • Author(s): Okuno H, Renault Mihara F, Ohta S, Fukuda K, Kurosawa K, Akamatsu W, Sanosaka T, Kohyama J, Hayashi K, Nakajima K, Takahashi T, Wysocka J, Kosaki K, Okano H.
  • Journal Title: Elife Volume: 6 Pages: 23-24
  • DOI: 10.7554/elife.21114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] STAT3: Down the R(h)oAd (2018)
  • Author(s): Renault-Mihara F, Okano H
  • Journal Title: Cytokine Volume: 102 Pages: 149-150
  • DOI: 10.1016/j.cyto.2017.08.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] STAT3: Down the R(h)oAd. (2018)
  • Author(s): Renault-Mihara F, Okano H
  • Journal Title: Cytokine Volume: 102 Pages: 149-150
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] STAT3-regulated RhoA drives reactive astrocyte dynamics. (2017)
  • Author(s): Renault-Mihara F, Okano H
  • Journal Title: Cell Cycle. Volume: 16 Pages: 1995-1996
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of RhoA by STAT3 coordinates glial scar formation. (2017)
  • Author(s): Renault-Mihara F, Mukaino M, Shinozaki M, Kumamaru H, Kawase S, Baudoux M, Ishibashi T, Kawabata S, Nishiyama Y, Sugai K, Yasutake K, Okada S, Nakamura M, Okano H.
  • Journal Title: J Cell Biol Volume: 216 Pages: 2533-2550
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Regulation of RhoA by STAT3 coordinates glial scar formation. (2017)
  • Author(s): Francois Renault-Mihara
  • Organizer: American Society of Cell Biology/European Molecular Biology Organization) 2017 meeting
  • Int'l Joint Research