A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells

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外文摘要：Cardiac biological pacing(BP)is one of the future directions for bradyarrhythmias intervention.Currently,cardiac pacemaker cells(PCs)used for cardiac BP are mainly derived from pluripotent stem cells(PSCs).However,the production of high-quality cardiac PCs from PSCs remains a challenge.Here,we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs.First,two PC markers,Shox2 and Hcn4,were selected to establish Shox2:EGFP;Hcn4:mCherry mouse PSC reporter line.Then,by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation,we designed the FSK method that increased the yield of SHOX2+;HCN4+cells with typical PC characteristics,which was 12 and 42 folds higher than that of the embryoid body(EB)and the monolayer M10 methods respectively.In addition,the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing(scRNA-seq),which resembled in vivo PCs development,and ZFP503 was verified as a key regulator of cardiac PCs differentiation.These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology,help with the understanding of PCs(patho)physiology,and benefit drug discovery for PC-related diseases as well.

作者：

Zheyi Lin、Bowen Lin、Chengwen Hang、Renhong Lu、Hui Xiong、Junyang Liu、Siyu Wang、Zheng Gong、Mingshuai Zhang、Desheng Li、Guojian Fang、Jie Ding、Xuling Su、Huixin Guo、Dan Shi、Duanyang Xie、Yi Liu、Dandan Liang、Jian Yang、Yi-Han Chen

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作者单位：

State Key Laboratory of Cardiovascular Diseases,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,China

Shanghai Arrhythmia Research Center,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,China

Department of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,China

Shanghai Frontiers Center of Nanocatalytic Medicine,Shanghai 200092,China

Department of Pathology and Pathophysiology,School of Medicine,Tongji University,Sh

Clinical Center for Heart Disease Research,Tongji University,Shanghai 200092,China

Department of Cardiology,The Second Hospital of Shanxi Medical University,Taiyuan 030001,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key Research and Development PlanProgram for the Research Unit of Origin and Regulation of Heart Rhythm,Chinese Academy of Medical SciencesTop-Level Clinical Discipline Project of Shanghai PudongKey Research Center Construction Project of ShanghaiShanghai Key Clinical Specialty ProjectNational Key Clinical Specialty and Fundamental Research Funds for the Central Universities to Y.-H.C

项目编号：

820881018193001331871491820703388222200882370396821220072019YFA08015012019RU045PWYgf2021-012022ZZ01008shslczdzk06202

出版年：

2024

DOI：

10.1038/s41392-024-01942-w

信号转导与靶向治疗(英文)

CSTPCD

ISSN：

年,卷(期)：2024.9(10)