Remodeling of the brain and meninges by Platelet-derived growth factor

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15415
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: University of Toyama
• Principal Investigator: Hamashima Takeru 富山大学, 学術研究部医学系, 助教 (80467092)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 脳血管障害 / 稀突起膠細胞 / 血小板由来増殖因子受容体 / 血管新生

Outline of Final Research Achievements

In the brains of conditional knockout mice (N-PRα-KO) of platelet-derived growth factor-α receptor (PDGFRα), PDGFRα-positive perivascular cells expanded their distribution from the meninges to the deep brain in a continuous perivascular fashion with increasing daily age, and fibroblasts perivascular fibroblasts (pvF) derived from the perivascular fibroblasts of the soft membrane. Single-cell analysis revealed the induction of pvF from meningeal perivascular fibroblasts and their transformation into active fibroblasts consistent with inflammatory tissue modification. Treatment with PDGFRα-neutralizing antibodies activated pvF downstream of border-associated macrophages and contributed to inflammatory tissue modification.

Free Research Field

実験病理

Academic Significance and Societal Importance of the Research Achievements

脳血管障害は日本人の死亡原因の上位を占め、死亡率や後遺症の残存率は依然として高く、予後の改善が急務である。
N-PRα-KO 脳で血管の脆弱性を確認したところ、IgG leakage の増加が見られたが、blood-brain-barrierの構成成分に変化は認めなかった。血管の脆弱性は旺盛な血管新生に伴うもの、もしくは稀突起膠細胞系譜細胞による保護の欠如に伴うと推測された。N-PRα-KO 脳皮質で大幅な炎症性の組織改変が確認された。髄膜の炎症性変化や脳における線維芽細胞の誘導は、多様な中枢神経疾患にいて報告されており、本研究はこれらの疾患予後改善の治療法確立に寄与するものとなりうる。