Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

Huiya Li,Lingzhen Wu,Yunling Lin,Shumei Li,Huashan Hong,Yukun Luo,Jun Fang,Danqing Hu,Tingxiang Lan,Dedong Zheng,Guilin Chen,Yilang Ke,Wenying Wang,Yu Huang

doi:10.1038/s41419-021-03610-1

Abstract

Both weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

Highlights

Stem cell therapy to repair infarcted myocardium is generally established as a promising strategy to treat heart failure, and the paracrine effects may be a more important mechanism than myocardial regeneration[1,2,3,4].The success of the cell therapy has been compromised by a dual dilemma of the low survival rate of donor cells and hostile host microenvironment[1,4,5,6,7,8,9]
A secreted protein encoded by the energy homeostasis-associated gene[11], has been identified as a novel endogenous bioactive factor to protect endothelial function through the pro-survival reperfusion injury salvage kinase (RISK) pathway[12], which consists of phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular regulated protein kinases (ERK) 1/2 pathways[13]
Various doses of adropin were used to investigate its effects on the H2O2-induced apoptosis of mesenchymal stem cells (MSCs)

Summary

Introduction

Stem cell therapy to repair infarcted myocardium is generally established as a promising strategy to treat heart failure, and the paracrine effects may be a more important mechanism than myocardial regeneration[1,2,3,4]. The success of the cell therapy has been compromised by a dual dilemma of the low survival rate of donor cells (the “seed”) and hostile host microenvironment (the “soil”)[1,4,5,6,7,8,9]. To achieve ideal therapeutic efficiency, stem cell therapy should seek a new strategy that adopts a synergistic manner to target the “seed” to improve the survival potential and the “soil” to modify the hostile microenvironment in myocardial infarction (MI)[8,10]. The research on dual protective strategies for stem cell therapy remains limited.

Methods

Results

Conclusion