Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.
Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.
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DOI：
10.1172/jci.insight.155640
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发表时间：
2022-04-08
期刊：
影响因子：
8
通讯作者：
Darbar, Dawood
中科院分区：
文献类型：
--
作者：
Ly, Olivia T.;Chen, Hanna;Brown, Grace E.;Hong, Liang;Wang, Xinge;Han, Yong Duk;Pavel, Mahmud Arif;Sridhar, Arvind;Maienschein-Cline, Mark;Chalazan, Brandon;Ong, Sang-Ging;Abdelhady, Khaled;Massad, Malek;Rizkallah, Lona Ernst;Rehman, Jalees;Khetani, Salman R.;Darbar, Dawood
Human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs. Using the patient’s own atrial tissue as a gold standard benchmark, we assessed the electrophysiological, structural, metabolic, and molecular maturation of iPSC-aCMs. Unbiased transcriptomic analysis and inference from gene regulatory networks identified key gene expression pathways and transcription factors mediating atrial development and maturation. Only mature iPSC-aCMs generated from patients with heritable AF carrying the non-ion channel gene (NPPA) mutation showed enhanced expression and function of a cardiac potassium channel and revealed mitochondrial electron transport chain dysfunction. Collectively, we propose that ion channel remodeling in conjunction with metabolic defects created an electrophysiological substrate for AF. Overall, our electro-metabolic approach generated mature human iPSC-aCMs that unmasked the underlying mechanism of the first non-ion channel gene, NPPA, that causes AF. Our maturation approach will allow for the investigation of the molecular underpinnings of heritable AF and the development of personalized therapies.
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影响因子：
16.6
作者：
Funakoshi S;Fernandes I;Mastikhina O;Wilkinson D;Tran T;Dhahri W;Mazine A;Yang D;Burnett B;Lee J;Protze S;Bader GD;Nunes SS;Laflamme M;Keller G
通讯作者：
Keller G
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
20.1
作者：
Ackers-Johnson M;Li PY;Holmes AP;O'Brien SM;Pavlovic D;Foo RS
通讯作者：
Foo RS
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
DOI：
10.1073/pnas.0337639100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Czubryt, MP;McAnally, J;Olson, EN
通讯作者：
Olson, EN