Tongxinluo-pretreated mesenchymal stem cells facilitate cardiac repair via exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway

Yuyan Xiong; Ruijie Tang; Junyan Xu; Wenyang Jiang; Zhaoting Gong; Lili Zhang; Yu Ning; Peisen Huang; Jun Xu; Guihao Chen; Xiaosong Li; Mengjin Hu; Jing Xu; Chunxiao Wu; Chen Jin; Xiangdong Li; Haiyan Qian; Yuejin Yang

doi:10.1186/s13287-022-02969-y

Tongxinluo-pretreated mesenchymal stem cells facilitate cardiac repair via exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway

Stem Cell Res Ther. 2022 Jul 7;13(1):289. doi: 10.1186/s13287-022-02969-y.

Authors

Yuyan Xiong¹, Ruijie Tang¹, Junyan Xu¹, Wenyang Jiang¹, Zhaoting Gong¹, Lili Zhang¹, Yu Ning¹, Peisen Huang¹, Jun Xu¹, Guihao Chen¹, Xiaosong Li¹, Mengjin Hu¹, Jing Xu¹, Chunxiao Wu¹, Chen Jin¹, Xiangdong Li¹, Haiyan Qian¹, Yuejin Yang²

Affiliations

¹ State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China.
² State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China. yangyuejin@fuwai.com.

Abstract

Background: Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCs^TXL) in enhancing cardiac repair and further investigated the underlying mechanism.

Methods: MSCs^TXL or MSCs and the derived exosomes (MSCs^TXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCs^TXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism.

Results: Compared to MSCs, MSCs^TXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCs^TXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCs^TXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury.

Conclusions: This study suggested that MSCs^TXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation.

Keywords: Exosomes; Mesenchymal stem cells; Myocardial infarction; Pretreatment; Tongxinluo.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drugs, Chinese Herbal
Exosomes* / metabolism
Interleukin-1 Receptor-Associated Kinases* / metabolism
Mesenchymal Stem Cells* / metabolism
MicroRNAs* / genetics
Myocardial Infarction* / genetics
Myocardial Infarction* / pathology
Myocardial Infarction* / therapy
Rats
Stroke Volume
Transcription Factor RelA* / metabolism
Ventricular Function, Left

Substances

Drugs, Chinese Herbal
MIRN146 microRNA, rat
MicroRNAs
Rela protein, rat
Transcription Factor RelA
tongxinluo
IRAK1 protein, rat
Interleukin-1 Receptor-Associated Kinases