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Investigation of association between adipocytes and vasculopathy of systemic sclerosis by Fli1 knockout model

Research Project

Project/Area Number 19K24041
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0906:Surgery related to the biological and sensory functions and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Miyagawa Takuya  東京大学, 医学部附属病院, 助教 (60843323)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords全身性強皮症 / 血管障害 / 脂肪細胞
Outline of Research at the Start

全身性強皮症は線維化、血管障害、免疫異常を特徴とした自己免疫疾患であり、近年その血管障害の病態と様々なアディポカインとの関与が指摘されている。また全身性強皮症の病因は不明なものの、転写因子Fli1の恒常的発現低下が疾患素因の1つとして考えられている。そこで我々は、脂肪細胞が全身性強皮症の血管障害とどのように関わっているかを調べるため、脂肪細胞特異的Fli1欠損マウスを作成し、全身性強皮症様の血管障害を発症するか、また発症する場合はその機序に関して検討を行うこととした。この検討により脂肪細胞の全身性強皮症への寄与が明らかになるとともに、同疾患に対する新規薬剤開発につながるものと考えた。

Outline of Final Research Achievements

Association between adipocytes and vasculopathy of systemic sclerosis (SSc) remains to be seen. We generated adipocyte-specific Fli1 knockout (Fli1 AdipoKO) mice and investigated whether and how vasculopathy is induced. Fli1 AdipoKO mice exhibited vascular structural and functional abnormalities as early as 3 months of age. Bone marrow-derived mesenchymal stem cells (BM-MSCs) of Fli1 AdipoKO mice exhibited de-differentiated phenotype, suggesting the contribution of defective vasculogenesis to the development of vascular abnormalities. This phenotype was induced by co-culture of Fli1-deficient adipocytes and BM-MSCs of wild type mice. Furthermore, upregulated IL-6 induced by Fli1-deficient adipocytes changed BM-MSCs of wild type mice into de-differentiated phenotype. These results indicate that Fli1-deficient adipocytes can be involved in the development of vasculopathy recapitulating SSc, suggesting a contribution of phenotypically altered adipocytes to the development of SSc.

Academic Significance and Societal Importance of the Research Achievements

今まで明らかになっていなかった全身性強皮症の血管障害と脂肪細胞の関連が本研究によって示唆された。また全身性強皮症の血管障害の病態にもIL-6が関与している可能性があり、抗IL-6抗体による治療が線維化のみならず血管障害の改善にも寄与する可能性があることが示唆された。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (1 results)

All 2020

All Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] Fli1-deficient adipocytes promote spontaneous skin fibrosis and vasculopathy: potential roles of adipocytes in systemic sclerosis2020

    • Author(s)
      Takuya Miyagawa
    • Organizer
      Systemic sclerosis world congress
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research

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Published: 2019-09-03   Modified: 2022-01-27  

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