Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.
Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.
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DOI：
10.1016/j.stemcr.2023.07.005
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发表时间：
2023-09-12
影响因子：
5.9
通讯作者：
Pu, William T.
中科院分区：
文献类型：
--
作者：
Kim, Sean L.;Trembley, Michael A.;Lee, Keel Yong;Choi, Suji;Macqueen, Luke A.;Zimmerman, John F.;Wit, Lousanne H. C. de;Shani, Kevin;Henze, Douglas E.;Drennan, Daniel J.;Saifee, Shaila A.;Loh, Li Jun;Liu, Xujie;Parker, Kevin Kit;Pu, William T.
致心律失常性心肌病（ACM）是一种遗传性心脏疾病，可导致危及生命的心律失常和心肌功能障碍。Plakophilin-2（PKP 2）中的致病性变体，一种专门的心脏细胞连接中的桥粒组分，引起大多数ACM病例。然而，PKP 2变异体诱导疾病表型的分子机制仍不清楚。在这里，我们使用基因修饰的人诱导多能干细胞衍生的心肌细胞构建生物工程平台，以模拟体外心肌细胞连接组装的早期时空过程。截短变体PKP 2 R413 X的杂合性降低了Wnt/β-连环蛋白信号传导，损害了肌原纤维形成，延迟了机械偶联，并降低了工程化组织中的钙波速度。SB 216763可以改善这些异常，它可以激活Wnt/β-catenin信号，改善细胞骨架组织，恢复细胞对中细胞连接的完整性，并改善工程组织中的钙波速度。总之，这些发现突出了在人类ACM模型中调节Wnt/β-catenin信号的治疗潜力。表征hiPSC-CM细胞对中细胞连接的时空组装ACM致病性变体损害细胞骨架和细胞连接自组装ACM致病性变体降低工程化心脏组织中的钙波速度SB 216763激活Wnt/β-连环蛋白恢复了这些体外ACM表型Pu et al.研究致病性心肌病变异体对细胞-细胞连接结构和功能的影响。使用由人类诱导多能干细胞衍生的心肌细胞组装的生物工程组织，研究小组表明，这种变异损害了细胞间连接的形成，减缓了心脏冲动的传播。
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2R413X reduced Wnt/β-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/β-catenin signaling, improved cytoskeletal organization, restored cell junction integrity in cell pairs, and improved calcium wave velocity in engineered tissues. Together, these findings highlight the therapeutic potential of modulating Wnt/β-catenin signaling in a human model of ACM. Characterized the spatiotemporal assembly of cell junctions in hiPSC-CM cell pairs ACM pathogenic variant compromised cytoskeletal and cell junction self-assembly ACM pathogenic variant reduced calcium wave velocity in engineered cardiac tissues Wnt/β-catenin activation by SB216763 restored these in vitro ACM phenotypes Pu et al. investigate the effect of a pathogenic arrhythmic cardiomyopathy variant on cell-cell junction structure and function. Using bioengineered tissues assembled from human induced pluripotent stem cell-derived cardiomyocytes, the team showed that the variant impaired cell-cell junction formation and slowed cardiac impulse propagation.
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DOI：
10.1126/science.abh0474
发表时间：
2022-02-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lee KY;Park SJ;Matthews DG;Kim SL;Marquez CA;Zimmerman JF;Ardoña HAM;Kleber AG;Lauder GV;Parker KK
通讯作者：
Parker KK
影响因子：
64.8
作者：
通讯作者：
--
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：
5.9
作者：
Inoue H;Nakamura S;Higo S;Shiba M;Kohama Y;Kondo T;Kameda S;Tabata T;Okuno S;Ikeda Y;Li J;Liu L;Yamazaki S;Takeda M;Ito E;Takashima S;Miyagawa S;Sawa Y;Hikoso S;Sakata Y
通讯作者：
Sakata Y
影响因子：
8
作者：
Chelko, Stephen P.;Asimaki, Angeliki;Judge, Daniel P.
通讯作者：
Judge, Daniel P.