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Bio-Design and Manufacturing  2025 Vol.8 No.1 P.20-35

http://doi.org/10.1631/bdm.2400168


Testosterone Prompted Cardiac Fibrosis in Arrhythmogenic Right Ventricular Cardiomyopathy: Evidence from Clinical to the in vitro Human iPSC-derived Engineered Cardiac Spheroids


Author(s):  Hongyi Cheng, Xinrui Wang, Sichong Qian, Yike Zhang, Jincheng Jiao, Bingyu Zheng, Yue Zhu, Hua Xu, Jia Song, Feng Zhang, Xiaohong Jiang, Chang Cui, Minglong Chen

Affiliation(s):  Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China; more

Corresponding email(s):   cuichang@njmu.edu.cn, jiangxiaohong0326@163.com, 591671366@qq.com

Key Words:  ARVC, Gender Difference, Cardiac Spheroids, Testosterone, Fibrosis


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Hongyi Cheng, Xinrui Wang, Sichong Qian, Yike Zhang, Jincheng Jiao, Bingyu Zheng, Yue Zhu, Hua Xu, Jia Song, Feng Zhang, Xiaohong Jiang, Chang Cui, Minglong Chen. Testosterone Prompted Cardiac Fibrosis in Arrhythmogenic Right Ventricular Cardiomyopathy: Evidence from Clinical to the in vitro Human iPSC-derived Engineered Cardiac Spheroids[J]. Journal of Zhejiang University Science D, 2025, 8(1): 20-35.

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author="Hongyi Cheng, Xinrui Wang, Sichong Qian, Yike Zhang, Jincheng Jiao, Bingyu Zheng, Yue Zhu, Hua Xu, Jia Song, Feng Zhang, Xiaohong Jiang, Chang Cui, Minglong Chen",
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%A Hongyi Cheng
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%A Yike Zhang
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%A Hua Xu
%A Jia Song
%A Feng Zhang
%A Xiaohong Jiang
%A Chang Cui
%A Minglong Chen
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A1 - Sichong Qian
A1 - Yike Zhang
A1 - Jincheng Jiao
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A1 - Yue Zhu
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A1 - Jia Song
A1 - Feng Zhang
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A1 - Chang Cui
A1 - Minglong Chen
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Abstract: 
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a progressive disease characterized by adipose and fibrous replacement of the myocardium. Elevated testosterone levels may contribute to the pathological process in ARVC patients. However, the exact contribution of testosterone to cardiac fibrosis in ARVC remains unclear. In this study, we analyzed the gender Differences in the distribution of the low-voltage area in an ARVC cohort undergoing an electrophysiological study, and feature selection suggested the potential contribution of gender Differences in the low-voltage areas in ARVC patients. Additionally, we established engineered cardiac Spheroids models in vitro using patient-specific induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and fibroblasts (icFBs), and elucidated the pathogenicity of abnormal splicing in the PKP2 gene caused by an intronic mutation. The additional pathogenic validation of the Desmoglein2 (DSG2) point mutation further confirms the reliability of the models. Moreover, testosterone exacerbated the DNA damage in the mutated cardiomyocytes (CMs) and further activated myofibroblasts as a chain reaction. In conclusion, we designed and constructed an in vitro 3D engineered cardiac spheroid model of ARVC based on clinical findings and provided direct evidence of the fibrotic role of testosterone in ARVC.

睾酮加重遗传性心肌病心脏类器官球体纤维化

作者:程弘毅1,2,王心睿3,4,钱思翀1,焦锦程1,6,郑冰玉1,竺悦1
机构:1南京医科大学第一附属医院心内科,中国南京市,210029;2南京医科大学姑苏学院,中国苏州市,215002;3福建医科大学妇儿临床医学院,中国福州市,350122;4福建省妇幼保健院福建省妇儿重大疾病研究重点实验室,中国福州市,350001;5北京安贞医院心脏外科,中国北京市,100029;6东南大学生物科学与医学工程学院数字医学工程全国重点实验室,中国南京市, 210096;7贝勒医学院,美国休斯顿,77030;8南京医科大学心血管病转化医学协同创新中心江苏省心血管病靶向干预研究重 点实验室,中国南京市,210029
摘要:致心律失常性右室心肌病(ARVC)是一种遗传性心肌病,进行性脂肪纤 维化是其独特特征。升高的睾酮水平可能会促进 ARVC 的纤维化病理过程。然 而,因为缺乏良好的遗传性心肌病模型,睾酮对 ARVC 心脏纤维化的具体作用 仍不明确。此研究首先在接受了临床电生理标测的 ARVC 患者中明确了纤维化 低电压区分布的性别差异,接着使用患者特异性诱导多能干细胞来源的心肌细胞 和心脏成纤维细胞构建了三维心脏类器官球体模型,进而在该模型上使用睾酮进 行了药物试验。与动物模型比,体外的心脏类器官球体平台具有更好的代表性, 观察疾病表型更加直观便捷。同时基于诱导多能干细胞分化的多种细胞类型构建 的心脏类器官是更加生理化的多细胞共培养模型,可用于探究细胞间相互作用的 机制,明确致病的靶细胞和靶分子,有利于遗传性心肌病的精准干预。总之,该 研究建立了一种新的 ARVC 体外三维模型,并提供了直接证据表明睾酮在 ARVC 中起到了促纤维化的作用。

关键词:致心律失常性右室心肌病;性别差异;心脏类器官球体;睾酮;纤维化

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