TBX20 Improves Contractility and Mitochondrial Function During Direct Human Cardiac Reprogramming

Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails, and the underlying mol...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) Vol. 146; no. 20; p. 1518
Main Authors: Tang, Yawen, Aryal, Sajesan, Geng, Xiaoxiao, Zhou, Xinyue, Fast, Vladimir G, Zhang, Jianyi, Lu, Rui, Zhou, Yang
Format: Journal Article
Language:English
Published: United States 15.11.2022
Subjects:
Cardiovascular Agents - pharmacology
Cardiovascular Agents - therapeutic use
Cellular Reprogramming - drug effects
Cellular Reprogramming - genetics
Cellular Reprogramming - physiology
Chromatin - genetics
Chromatin - metabolism
Fibroblasts - drug effects
Fibroblasts - metabolism
Fibroblasts - physiology
Humans
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - physiology
Myocardial Contraction - drug effects
Myocardial Contraction - genetics
Myocardial Contraction - physiology
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
T-Box Domain Proteins - genetics
T-Box Domain Proteins - metabolism
myocytes, cardiac
fibroblasts
regeneration
transcription factors
heart
cellular reprogramming
ISSN:1524-4539, 1524-4539
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Summary:Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails, and the underlying molecular mechanisms are not well studied. To discover potential missing factors for human direct reprogramming, we performed transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes. We identified (T-box transcription factor 20) as the top cardiac gene that is unable to be activated by the MGT133 reprogramming cocktail ( , , , and ). TBX20 is required for normal heart development and cardiac function in adult cardiomyocytes, yet its role in cardiac reprogramming remains undefined. We show that the addition of TBX20 to the MGT133 cocktail (MGT+TBX20) promotes cardiac reprogramming and activates genes associated with cardiac contractility, maturation, and ventricular heart. Human induced cardiomyocytes produced with MGT+TBX20 demonstrated more frequent beating, calcium oscillation, and higher energy metabolism as evidenced by increased mitochondria numbers and mitochondrial respiration. Mechanistically, comprehensive transcriptomic, chromatin occupancy, and epigenomic studies revealed that TBX20 colocalizes with MGT reprogramming factors at cardiac gene enhancers associated with heart contraction, promotes chromatin binding and co-occupancy of MGT factors at these loci, and synergizes with MGT for more robust activation of target gene transcription. TBX20 consolidates MGT cardiac reprogramming factors to activate cardiac enhancers to promote cardiac cell fate conversion. Human induced cardiomyocytes generated with TBX20 showed enhanced cardiac function in contractility and mitochondrial respiration.
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ISSN:1524-4539
1524-4539
DOI:10.1161/CIRCULATIONAHA.122.059713