The fibrotic extracellular matrix induces release of extracellular vesicles with pro-fibrotic miRNA from fibrocytes

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: The University of Tokushima
• Principal Investigator: SATO Seidai 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (80530899)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Fibrocyte / 間質性肺炎 / 細胞外基質 / microRNA / miR-21 / 細胞外小胞体

Outline of Final Research Achievements

Extracellular vesicles (EVs) are small lipid vesicles, and EV-coupled miRNAs are important modulators of biological processes. Fibrocytes are circulating bone marrow-derived cells that migrate into the injured lungs and contribute to fibrogenesis. The question of whether EV-coupled miRNAs derived from fibrocytes are able to regulate pulmonary fibrosis has not been addressed yet. In this study, we demonstrated follow four facts; (1) the EVs of fibrocytes derived from fibrotic lungs significantly upregulated the expression of col1a1 of fibroblasts (2) Culturing on rigid plates or fibrotic decellularized lung scaffolds increased miR-21-5p expression, (3) Dissolved ECM collected from fibrotic lungs and recombinant TGF-beta1 increased miR-21-5p expression on fibrocytes (4) Fibrocytes from BALF collected from fibrotic interstitial pneumonia patients showed higher miR-21-5p expression than those from other patients.

Free Research Field

呼吸器内科学分野

Academic Significance and Societal Importance of the Research Achievements

これまでの肺線維症治療は線維芽細胞の増殖に関わる増殖因子を標的としてきた。細胞外基質（ECM）成分が種々の細胞機能に影響を与えることは広く知られているが、ECMを標的とした治療戦略は、肺線維症分野において試みられたことがない。本研究は、線維化肺組織におけるECMが、線維細胞のmiRNA発現を変化させて更なる線維化進行に寄与するというメカニズムを実証し、その制御による新たな治療戦略の開発を目指すことを目的としている。これにより新たな線維化促進メカニズムを同定できれば、肺線維症を含む各種線維性疾患において、従来の治療戦略とは重複しない新たな治療戦略の開発に結び付く可能性がある。