Pathological functions of cardiac fibroblasts in pediatric cardiomyopathy

• Project/Area Number: 18K07789
• 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, 医学系研究科, 助教 (90794008)
• Co-Investigator(Kenkyū-buntansha): 石田 秀和 大阪大学, 医学系研究科, 助教 (50467552) ; 小垣 滋豊 大阪大学, 医学系研究科, 招へい教員 (00311754)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心筋症 / 心筋線維芽細胞 / 心筋細胞 / 遺伝子発現解析 / 心臓移植 / 拡張型心筋症 / RNA-seq / 拘束型心筋症

Outline of Final Research Achievements

The precise molecular mechanisms of idiopathic cardiomyopathy is still unknown. We performed whole exome analysis for Japanese pediatric cardiomyopathy patients and identified lots of gene mutations which cause cardiomyopathy in children. We cultured cardiac fibroblasts obtained from the various cardiomyopathy patients while the heart transplantation or ventricular assist device implantation. The diseased cardiac fibroblasts show significant different gene expression patterns as compared to the healthy cardiac fibroblasts. When we co-cultured the healthy cardiomyocytes with diseased cardiac fibroblasts, the cardiomyocytes showed weaken contraction and dilatation ability. We established induced pluripotent stem cell lines from the patients with idiopathic cardiomyopathy in children.

Academic Significance and Societal Importance of the Research Achievements

今回の私達の研究により、これまで心筋細胞にのみ原因があると考えられてきた特発性心筋症の病態において、心筋線維芽細胞が重要な役割を果たしていることが明らかとなった。心筋症の患者から得られた心筋線維芽細胞が、健常な心筋細胞の収縮能や拡張能に悪影響を与えているということは大きな発見である。今後、心筋細胞だけでなく心筋線維芽細胞もターゲットとした新しい治療法の開発につながる可能性がある。

Research Products

• [Journal Article] Cardiac Fibroblasts Play Pathogenic Roles in Idiopathic Restrictive Cardiomyopathy (2021)
  • Author(s): Tsuru Hirofumi、Ishida Hidekazu、Narita Jun、Ishii Ryo、Suginobe Hidehiro、Ishii Yoichiro、Wang Renjie、Kogaki Shigetoyo、Taira Masaki、Ueno Takayoshi、Miyashita Yohei、Kioka Hidetaka、Asano Yoshihiro、Sawa Yoshiki、Ozono Keiichi
  • Journal Title: Circulation Journal Volume: 85 Issue: 5 Pages: 677-686
  • DOI: 10.1253/circj.CJ-20-1008
  • NAID: 130008028981
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2021-04-23
  • Peer Reviewed / Open Access
• [Presentation] 小児心筋症における心筋線維芽細胞の生理機能ならびに病態関与の解析 (2020)
  • Author(s): 水流宏文, 石田秀和, 杉辺英世, 桂木慎一, 石井 良, 成田 淳, 上野高義, 小垣滋豊, 澤 芳樹, 大薗恵一
  • Organizer: 第56回 日本小児循環器学会学術集会
• [Presentation] 心筋線維芽細胞に着目した小児心筋症の病態解明と治療応用 (2019)
  • Author(s): 水流宏文、石井良ら
  • Organizer: 第55回 日本小児循環器学会総会