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

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17638
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: The University of Tokushima
• Principal Investigator: SATO Seidai 徳島大学, 病院, 講師 (80530899)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: fibrocyte / 間質性肺炎 / 細胞外基質 / microRNA / miR-21 / 細胞外小胞

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 demonstrate that (1) fibrocytes exert pro-fibrotic effects on fibroblasts through secretion of EVs containing pro-fibrotic miRNA; and (2) that the abnormal ECM in fibrotic lung increases the expression of pro-fibrotic miRNA from fibrocytes. These findings suggest that abnormal ECM in pulmonary fibrosis is able to self-promote fibrosis by inducing fibrogenic miRNA from fibrocytes. This complex and dynamic process of the interaction between circulating fibrocytes with their cellular and molecular microenvironment in the lungs should be integrated into novel therapeutic strategies of fibrosis.

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つく可能性がある。