Engineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions

Pengcheng Yang, Lihang Zhu, Shiya Wang, Jixing Gong, Jonathan Nimal Selvaraj, Lincai Ye, Hanxiao Chen, Yaoyao Zhang, Gongxin Wang, Wanjun Song, Zilong Li, Lin Cai (), Hao Zhang () and Donghui Zhang ()
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Pengcheng Yang: Hubei University
Lihang Zhu: Wuhan University
Shiya Wang: Hubei University
Jixing Gong: Sun Yat‐Sen University
Jonathan Nimal Selvaraj: Hubei University
Lincai Ye: National Children’s Medical Center
Hanxiao Chen: West China Second University Hospital, Sichuan University
Yaoyao Zhang: West China Second University Hospital, Sichuan University
Gongxin Wang: Henan SCOPE Research Institute of Electrophysiology Co. Ltd.
Wanjun Song: Beijing Geek Gene Technology Co. Ltd.
Zilong Li: Hubei University
Lin Cai: Hubei University
Hao Zhang: National Children’s Medical Center
Donghui Zhang: Hubei University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFβ inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.

Date: 2024
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DOI: 10.1038/s41467-024-52221-9

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