The analysis of vasculopathy in systemic sclerosis with the mice lacking the Fli1 gene in macrophages

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22972
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Fukui Yuki 東京大学, 医学部附属病院, 助教 (10880198)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 全身性強皮症 / 創傷治癒 / マクロファージ

Outline of Final Research Achievements

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by vasculopathy and fibrosis of the skin and various internal organs. Previous studies have shown that the deficiency of transcription factor Fli1 induces SSc-like phenotypes in dermal fibroblasts, endothelial cells, and macrophages. In this study, we generated myeloid cell-specific Fli1 knockout mice (Fli1 McKO mice) and investigated whether this animal model reproduces SSc-like vasculopathy. Fli1 McKO mice recapitulated structural and functional abnormalities of SSc vasculopathy. Furthermore, wound healing was delayed in Fli1 McKO mice due to loss of newly formed blood vessels. In vitro experiments, the migratory activities were enhanced, while the tubulogenic activity was reduced in human dermal microvascular endothelial cells (HDMECs) co-cultured with macrophages isolated from Fli1 McKO mice. These results indicate that Fli1-deficient macrophages involve in the development of vasculopathy recapitulating SSc.

Free Research Field

全身性強皮症

Academic Significance and Societal Importance of the Research Achievements

全身性強皮症の血管障害と創傷治癒遅延における単球、マクロファージの役割について現時点では不明とされている。本研究では、ヒトでの検討が困難な血管障害の病態解析に全身性強皮症の病態を忠実に再現するFli1 McKOマウスを用いることで、マクロファージが新生血管の不安定化を誘導し、血管形成の障害や創傷治癒遅延の病態形成に関与する可能性を明らかにした。本研究成果は、全身性強皮症の血管障害においてマクロファージをターゲットとした新規治療開発の一助となることが期待される。