Theranostics 2021; 11(1):268-291. doi:10.7150/thno.47021

Research Paper

Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction

Zhaofu Liao1*, Yilin Chen2,3,4,5*, Chuncui Duan2,3,4,5, Kuikui Zhu2,3,4,5, Ruijin Huang6, Hui Zhao7, Maik Hintze6,8, Qin Pu6, Ziqiang Yuan9, Luocheng Lv2,3,4,5, Hongyi Chen2,3,4,5, Binglin Lai2,3,4,5, Shanshan Feng2,3,4,5, Xufeng Qi2,3,4,5✉, Dongqing Cai2,3,4,5✉

1. The First Affiliated Hospital, Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou 510632, China.
2. Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou 510632, China.
3. Joint Laboratory for Regenerative Medicine, Chinese University of Hong Kong-Jinan University, Guangzhou 510632, China.
4. International Base of Collaboration for Science and Technology (JNU), Ministry of Science and Technology, Guangdong Province, Guangzhou 510632, China.
5. Department of Developmental and Regenerative Biology, Jinan University, Guangzhou 510632, China.
6. Institute of Anatomy, Department of Neuroanatomy, University of Bonn, Germany.
7. Stem Cell and Regeneration TRP, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.
8. Medical Department, MSH Medical School Hamburg, Germany.
9. Cancer Institute of New Jersey, Department of Medical Oncology, Robert Wood Johnson of Medical School, USA.
*Equal contributions to this work.

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Citation:
Liao Z, Chen Y, Duan C, Zhu K, Huang R, Zhao H, Hintze M, Pu Q, Yuan Z, Lv L, Chen H, Lai B, Feng S, Qi X, Cai D. Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction. Theranostics 2021; 11(1):268-291. doi:10.7150/thno.47021. Available from http://www.thno.org/v11p0268.htm

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Abstract

Promotion of cardiac angiogenesis in ischemic myocardium is a critical strategy for repairing and regenerating the myocardium after myocardial infarction (MI). Currently, effective methods to aid in the survival of endothelial cells, to avoid apoptosis in ischemic myocardium and to achieve long-term cardiac angiogenesis are still being pursued. Here, we investigated whether cardiac telocyte (CT)-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells to facilitate cardiac angiogenesis during MI.

Methods: CT exosomes were isolated from CT conditioned medium, and their miRNA profile was characterized by small RNA sequencing. A rat model of left anterior descending coronary artery ligation (LAD)-mediated MI was assessed with histology for infarct size and fibrosis, immunostaining for angiogenesis and cell apoptosis and echocardiography to evaluate the therapeutic effects. Cardiac microvascular endothelial cells (CMECs) and the LAD-MI model treated with CT exosomes or CT exosomal miRNA-21-5p in vitro and in vivo were assessed with cellular and molecular techniques to demonstrate the underlying mechanism.

Results: CTs exert therapeutic effects on MI via the potent paracrine effects of CT exosomes to facilitate the inhibition of apoptosis and survival of CMECs and promote cardiac angiogenesis. A novel mechanism of CTs is revealed, in which CT-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells in the pathophysiological myocardium. CT exosomal miRNA-21-5p targeted and silenced the cell death inducing p53 target 1 (Cdip1) gene and thus down-regulated the activated caspase-3, which then inhibited the apoptosis of recipient endothelial cells under ischemic and hypoxic conditions, facilitating angiogenesis and regeneration following MI.

Conclusions: The present study is the first to show that CTs inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted Cdip1 silencing to improve angiogenesis in myocardial infarction. It is believed that these novel findings and the discovery of cellular and molecular mechanisms will provide new opportunities to tailor novel cardiac cell therapies and cell-free therapies for the functional and structural regeneration of the injured myocardium.

Keywords: cardiac telocytes, apoptosis of endothelial cells, regeneration of myocardial infarction, exosomal miR-21, Cdip1 gene