Establishment of cardiac pacemaker cells via direct reprogramming methods.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19359
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Ritsumeikan University
• Principal Investigator: Kawamura Teruhisa 立命館大学, 生命科学部, 教授 (90393199)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: ダイレクトリプログラミング / 心臓ペースメーカ細胞 / 再生医学

Outline of Final Research Achievements

Loss or dysfunction of cardiac pacemaker cells in sinus nodes leads to a severe bradyarrhythmia which requires mechanical pacemaker implantation. However, the strategy using the mechanical device harbors the problems such as infection, autonomic unresponsiveness, and expenditure. Thus, we attempted to create cardiac pacemaker cells converted from other cell types. First, fetal hearts were removed from the reporter mice expressing green fluorescence under the control of pacemaker cell-specific gene, Hcn4. RNA-seq was then performed to select the highly expressed genes in HCN4-positive cells. Second, fetal hearts were separated into four regions (atriums, atrioventricular canals, ventricles, and outflow tracts) and were subjected to ATAC-seq to examine the open chromatin regions in the genome. Genes highly expressed in cardiac pacemaker cells with atrium-specific open chromatin region were selected as candidates and tested for direct reprograming toward cardiac pacemaker cells.

Free Research Field

再生医学

Academic Significance and Societal Importance of the Research Achievements

遺伝子導入によるダイレクトリプログラミング法は、体細胞から機能成熟した細胞が得られると期待される。多能性幹細胞を用いた分化培養と比べて未分化細胞の除去や分化細胞の成熟化が省略され、時間と費用を節約できるため、臨床応用へ向けた基礎研究として意義深い。研究成果は、本邦で6 万件以上の移植術が行われる機械式ペースメーカの欠点を克服した新たなツールとして、生産者年齢から高齢まで幅広い患者の予後改善や生活の質の向上に大きく貢献すると期待される。さらに、本研究は未解明な心臓ペースメーカ組織の発生制御分子ネットワークの解明にも繋がり、学問的な芽生えとなる研究成果といえる。