Elucidation for the pathogenesis of pediatric dilated cardiomyopathy by focusing on the interaction between cardiomyocytes and cardiac fibroblasts

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07749
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Osaka University
• Principal Investigator: ISHII RYO 大阪大学, 大学院医学系研究科, 助教 (90794008)
• Co-Investigator(Kenkyū-buntansha): 石田 秀和 大阪大学, 大学院医学系研究科, 講師 (50467552)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 拡張型心筋症 / 心筋線維芽細胞 / 心筋細胞

Outline of Final Research Achievements

Primary cultured cardiac fibroblast (CF) cell lines were established from pediatric dilated cardiomyopathy (DCM) patients and compared with three CF lines from healthy controls. When DCM-CFs were co-cultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA-sequencing revealed markedly different comprehensive gene expression profiles in DCM-CFs compared with healthy-CFs. Several humoral factors and the extracellular matrix (ECM) were significantly upregulated or downregulated in DCM-CFs. The pathway analysis revealed that ECM-receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor-beta signaling pathways were significantly affected in DCM-CFs. In contrast, single cell RNA-sequencing revealed that there was no specific subpopulation in the DCM-CFs that contributed to the alterations in gene expression.

Free Research Field

小児循環器学

Academic Significance and Societal Importance of the Research Achievements

本研究により、小児拡張型心筋症の病態形成において、心筋細胞だけではなく心筋線維芽細胞も重要な役割を果たしていることが明らかとなった。拡張型心筋症の心筋線維芽細胞は、遺伝子発現プロファイルが変容しており、細胞外マトリクスや接着因子シグナル、TGFβやHippoシグナルに大きな変化を起こしている。これらのシグナル経路の変化により、健常な心筋細胞との共培養においても、心筋細胞の収縮能および拡張能の増悪を来たす。この成果は、今後拡張型心筋症の新規治療開発において、心筋線維芽細胞をターゲットとした治療法につながると考えられる。