Theranostics 2021; 11(9):4262-4280. doi:10.7150/thno.52309

Research Paper

Thymosin β4 released from functionalized self-assembling peptide activates epicardium and enhances repair of infarcted myocardium

Yong-li Wang1,2, Shu-na Yu1, Hao-ran Shen1, Hai-jie Wang1✉, Xue-ping Wu1, Qiang-li Wang1,3, Bin Zhou4, Yu-zhen Tan1✉

1. Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai 200032, China
2. Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
3. School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
4. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200032, China

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Wang Yl, Yu Sn, Shen Hr, Wang Hj, Wu Xp, Wang Ql, Zhou B, Tan Yz. Thymosin β4 released from functionalized self-assembling peptide activates epicardium and enhances repair of infarcted myocardium. Theranostics 2021; 11(9):4262-4280. doi:10.7150/thno.52309. Available from

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The epicardium plays an important role in cardiomyogenesis during development, while it becomes quiescent in adult heart during homeostasis. This study investigates the efficiency of thymosin β4 (Tβ4) release with RPRHQGVM conjugated to the C-terminus of RADA16-I (RADA-RPR), the functionalized self-assembling peptide (SAP), to activate the epicardium and repairing the infarcted myocardium.

Methods: The functionalized SAP was constituted with self-assembling motif, Tβ4-binding site, and cell adhesive ligand. Myocardial infarction (MI) models of the transgenic mice were established by ligation of the left anterior descending coronary artery. At one week after intramyocardial injection of Tβ4-conjugated SAP, the activation of the epicardium was assessed. At four weeks after implantation, the migration and differentiation of epicardium-derived cells (EPDCs) as well as angiogenesis, lymphangiogenesis and myocardial regeneration were examined.

Results: We found that the designer RADA-RPR bound Tβ4 and adhered to EPDCs and that Tβ4 released from the functionalized SAP could effectively activate the epicardium and induce EPDCs to differentiate towards cardiovascular cells as well as lymphatic endothelial cells. Moreover, SAP-released Tβ4 (SAP-Tβ4) promoted proliferation of cardiomyocytes. Furthermore, angiogenesis, lymphangiogenesis and myocardial regeneration were enhanced in the MI models at 4 weeks after delivery of SAP-Tβ4 along with attenuation of adverse myocardial remodeling and significantly improved cardiac function.

Conclusions: These results demonstrate that sustained release of Tβ4 from the functionalized SAP can activate the epicardium and effectively enhance the repair of infarcted myocardium. We believe the delivery of SAP-Tβ4 may be a promising strategy for MI therapy.

Keywords: self-assembling peptide, thymosin beta 4, epicardium, epicardium-derived cells, myocardial infarction