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.

Engineered human models of hearts are needed to study pathology and repair. Here, the authors develop a model which replicates the phased remodelling process. The model is then used to study signalling pathway modulators for their therapeutic potential in a mini-repair model.

Details

Title
Engineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions
Author
Yang, Pengcheng 1   VIAFID ORCID Logo  ; Zhu, Lihang 2 ; Wang, Shiya 1 ; Gong, Jixing 3 ; Selvaraj, Jonathan Nimal 1 ; Ye, Lincai 4   VIAFID ORCID Logo  ; Chen, Hanxiao 5 ; Zhang, Yaoyao 5 ; Wang, Gongxin 6 ; Song, Wanjun 7 ; Li, Zilong 1 ; Cai, Lin 1   VIAFID ORCID Logo  ; Zhang, Hao 4   VIAFID ORCID Logo  ; Zhang, Donghui 8   VIAFID ORCID Logo 

1  Hubei University, State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Wuhan, China (GRID:grid.34418.3a) (ISNI:0000 0001 0727 9022) 
2  Wuhan University, Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China (GRID:grid.49470.3e) (ISNI:0000 0001 2331 6153) 
3  Sun Yat‐Sen University, Center of Translational Medicine, The First Affiliated Hospital, Zhongshan School of Medicine, Guangdong, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
4  National Children’s Medical Center, Shanghai Institute for Congenital Heart Diseases, Shanghai Children’s Medical Center, Shanghai, China (GRID:grid.415626.2) (ISNI:0000 0004 4903 1529) 
5  West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Chengdu, China (GRID:grid.461863.e) (ISNI:0000 0004 1757 9397) 
6  Henan SCOPE Research Institute of Electrophysiology Co. Ltd., Kaifeng, China (GRID:grid.461863.e) 
7  Beijing Geek Gene Technology Co. Ltd., Beijing, China (GRID:grid.461863.e) 
8  Hubei University, State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Wuhan, China (GRID:grid.34418.3a) (ISNI:0000 0001 0727 9022); Huazhong University of Science and Technology, Cardiovascular Research Institute, Union Hospital, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
Pages
7996
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-52221-9
ProQuest document ID
3103679155
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.