YBX-1 mediated sorting of miR-133 into hypoxia/reoxygenation-induced EPC-derived exosomes to increase fibroblast angiogenesis and MEndoT

Fengxia Lin,Xiao Ke,Zhicong Zeng,Zijun Wu,Xun Hu,Xun Hu,Xiaoduo Zhang,Liang Li,Yinzhi Song,Zhiwen Li

doi:10.1186/s13287-019-1377-8

Abstract

BackgroundMyocardial fibrosis is a common pathophysiological change in cardiovascular disease, which can cause cardiac dysfunction and even sudden death. Excessively activated fibroblasts proliferate and secret excessive extracellular matrix (ECM) components, resulting in normal cardiac structural damage and cardiac fibrosis. We previously found that human endothelial progenitor cell (EPC)-derived exosomes, after hypoxia/reoxygenation (H/R) induction, could significantly increase the mesenchymal-endothelial transition (MEndoT) compared to normal culture EPC-derived exosomes. Exosomes have been shown to carry different nucleic acids, including microRNAs. However, the effects of microRNAs in EPC-derived exosomes on MEndoT and myocardial fibrosis remain unknown.MethodsEPCs were isolated from human peripheral blood, and fibroblasts were isolated from rat hearts, then transfected with miR-133 inhibitor, si-YBX-1, and ov-YBX-1 into EPCs. After H/R induction for 48 h, isolation and characterization of exosomes derived from human EPCs were performed. Finally, fibroblasts were treated by exosome at 48 h. The expression of miR-133 was measured by qRT-PCR; YBX-1 expression was measured by qRT-PCR and western blot. Angiopoiesis was measured by tube formation assay. Endothelial markers and fibrosis markers were measured by western blot.ResultsH/R treatment promoted miR-133 expression in EPCs and EPC-derived exosomes. miR-133 could be incorporated into exosomes and transmitted to cardiac fibroblasts, increasing the angiogenesis and MEndoT of cardiac fibroblasts. miR-133 silencing in H/R-induced EPCs could inhibit miR-133 expression in EPCs and EPCs-derived exosomes. miR-133 silencing in H/R-induced EPCs could inhibit the angiogenesis and MEndoT of cardiac fibroblasts and reverse the effect of H/R treatment. Additionally, miR-133 was specially sorted into H/R-induced EPC-derived exosomes via YBX-1. YBX-1 silencing inhibited miR-133 transfer and reduced fibroblast angiogenesis and MEndoT.ConclusionmiR-133 was specially sorted into H/R-induced EPC-derived exosomes via YBX-1 to increase fibroblast angiogenesis and MEndoT.

Highlights

IntroductionActivated fibroblasts proliferate and secret excessive extracellular matrix (ECM) components, resulting in normal cardiac structural damage and cardiac fibrosis
Myocardial fibrosis is a common pathophysiological change in cardiovascular disease, which can cause cardiac dysfunction and even sudden death
Results miR-133 expression is upregulated in H/R-induced endothelial progenitor cell (EPC) (H/R-EPC)-derived exosomes (H/R-EPC-exosomes) First, we found that the senescence and apoptosis in H/ R-induced EPC were obviously enhanced compared to normal cultured EPCs (Fig. 1a, b)

Summary

Introduction

Activated fibroblasts proliferate and secret excessive extracellular matrix (ECM) components, resulting in normal cardiac structural damage and cardiac fibrosis. Myocardial fibrosis is a common pathophysiological change in cardiovascular disease, which can cause cardiac dysfunction and even sudden death [1]. Fibroblasts proliferate and activate excessive secretion of extracellular matrix components, resulting in normal cardiac structural damage and cardiac fibrosis. When pathological damage occurs in the heart, fibroblasts undergo a mesenchymal-endothelial transition (MEndoT) to obtain endothelial cell-like functions and participate in angiogenesis in the cardiac injury area, which is a novel antifibrotic strategy to alleviate myocardial fibrosis [4]. The mechanism underlying the transformation of cardiac fibroblasts into endothelial cells during pathological heart damage remains unclear

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