Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies.
Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies.
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作者：
研究单基因线粒体心肌病可能会深入了解线粒体在心脏发育和疾病中的作用。在这里，我们将联合收割机患者来源的和基因工程的iPSCs与组织工程相结合，以阐明Barth综合征（BTHS）心肌病的病理生理学基础，BTHS是一种由基因Tafazzin（TAZ）突变引起的线粒体疾病。使用BTHS iPSC衍生的心肌细胞（iPSC-CM），我们定义了与TAZ突变相关的代谢，结构和功能异常。BTHS iPSC-CM组装稀疏和不规则的肌节，并且工程化BTHS“芯片上的心脏”组织收缩微弱。基因替换和基因组编辑证明TAZ突变对于这些表型是必要的和充分的。肌节组装和心肌收缩异常发生在正常的全细胞ATP水平的背景下。过量的活性氧物质将TAZ突变与受损的心肌细胞功能联系起来。我们的研究为Barth综合征的发病机制提供了新的见解，提出了新的治疗策略，并推进了基于iPSC的心肌病体外建模。
Studying monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combine patient-derived and genetically engineered iPSCs with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene Tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural, and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS “heart on chip” tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies, and advances iPSC-based in vitro modeling of cardiomyopathy.
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影响因子：
6.1
作者：
Grosberg A;Alford PW;McCain ML;Parker KK
通讯作者：
Parker KK
影响因子：
12.4
作者：
Kariko, Katalin;Muramatsu, Hiromi;Welsh, Frank A.;Ludwig, Janos;Kato, Hiroki;Akira, Shizuo;Weissman, Drew
通讯作者：
Weissman, Drew
影响因子：
4.6
作者：
Warren, Luigi;Ni, Yuhui;Wang, Jiwu;Guo, Xirong
通讯作者：
Guo, Xirong
DOI：
10.1126/science.1177350
发表时间：
2009-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Domian IJ;Chiravuri M;van der Meer P;Feinberg AW;Shi X;Shao Y;Wu SM;Parker KK;Chien KR
通讯作者：
Chien KR
影响因子：
30.8
作者：
Bione, S;DAdamo, P;Toniolo, D
通讯作者：
Toniolo, D