Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models.
Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models.
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DOI：
10.3390/genes14101864
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发表时间：
2023-09-25
期刊：
影响因子：
3.5
通讯作者：
Boheler, Kenneth R.
中科院分区：
文献类型：
--
作者：
Chua, Christianne J.;Morrissette-McAlmon, Justin;Tung, Leslie;Boheler, Kenneth R.
关键词：
心肌病（CMPs）是一个重要的医疗负担，是心力衰竭导致过早死亡的主要原因。目前认为，有几种cmp具有很强的遗传基础，包括心律失常性心肌病（ACM），它使患者易发生心律失常发作。已知编码桥粒蛋白的五个基因（PKP2、JUP、DSC2、DSG2和DSP）中的一个基因的变异会导致一个子集的ACM，我们将其分类为桥粒相关ACM （dACM）。从表型上看，这种疾病可导致年轻运动员的心源性猝死，并且在后期常伴有心肌纤维脂肪浸润。虽然桥粒体基因的致病性已经通过动物研究和有限的原代人类细胞供应得到了很好的证实，但这些系统存在缺陷，限制了它们的效用和对理解人类疾病的相关性。人类诱导多能干细胞（hipsc）已经成为体外模拟ACM的强大工具，可以克服这些挑战，因为它们代表了再现患者表型的心肌细胞（CMs）的可再生和可扩展来源。在这篇综述中，我们提供了dACM的概述，总结了在其他连接桥粒蛋白与该疾病的模型系统中的发现，并提供了在hipsc -心肌细胞（hiPSC-CM） dACM模型中进行的最新工作总结。在hiPSC-CM模型系统的背景下，我们强调了有助于我们理解疾病的新发现，并列举了研究的局限性、前景和方向，以考虑未来的进展。
Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to have a strong genetic basis, including arrhythmogenic cardiomyopathy (ACM), which predisposes patients to arrhythmic episodes. Variants in one of the five genes (PKP2, JUP, DSC2, DSG2, and DSP) encoding proteins of the desmosome are known to cause a subset of ACM, which we classify as desmosome-related ACM (dACM). Phenotypically, this disease may lead to sudden cardiac death in young athletes and, during late stages, is often accompanied by myocardial fibrofatty infiltrates. While the pathogenicity of the desmosome genes has been well established through animal studies and limited supplies of primary human cells, these systems have drawbacks that limit their utility and relevance to understanding human disease. Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for modeling ACM in vitro that can overcome these challenges, as they represent a reproducible and scalable source of cardiomyocytes (CMs) that recapitulate patient phenotypes. In this review, we provide an overview of dACM, summarize findings in other model systems linking desmosome proteins with this disease, and provide an up-to-date summary of the work that has been conducted in hiPSC-cardiomyocyte (hiPSC-CM) models of dACM. In the context of the hiPSC-CM model system, we highlight novel findings that have contributed to our understanding of disease and enumerate the limitations, prospects, and directions for research to consider towards future progress.
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DOI：
10.1093/ehjcr/ytab213
发表时间：
2021-06
期刊：
European heart journal. Case reports
影响因子：
--
作者：
Lao N;Laiq Z;Courson J;Al-Quthami A
通讯作者：
Al-Quthami A
影响因子：
17.1
作者：
Asimaki A;Kapoor S;Plovie E;Karin Arndt A;Adams E;Liu Z;James CA;Judge DP;Calkins H;Churko J;Wu JC;MacRae CA;Kléber AG;Saffitz JE
通讯作者：
Saffitz JE
影响因子：
7.8
作者：
Brodehl, Andreas;Rezazadeh, Saman;Gerull, Brenda
通讯作者：
Gerull, Brenda
影响因子：
3.9
作者：
Awad, Mark M;Dalal, Darshan;Judge, Daniel P
通讯作者：
Judge, Daniel P
影响因子：
4.1
作者：
Blazeski, Adriana;Lowenthal, Justin;Tung, Leslie
通讯作者：
Tung, Leslie