Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells

Ke Yang,Qiu Jing Chen,Jing Liu,Yu Song He,Wei Feng Shen,Xiao Qun Wang,Lin Lu

doi:10.1186/1475-2840-9-66

Ke Yang, Qiu Jing Chen + Show 5 more

Open Access

https://doi.org/10.1186/1475-2840-9-66

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Abstract

BackgroundAdvanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs). MSCs have a potential role in cell replacement therapy in acute myocardial infarction and ischemic cardiomyopathy. However, mechanisms of AGEs on MSCs are still not unveiled.MethodsReactive oxygen species (ROS), genes regulation, cell proliferation and migration have been detected by AGE-BSA stimulated MSCs.ResultsWe found that in vitro stimulation with AGE-BSA induced generation of reactive oxygen species (ROS), and inhibited dose-dependently proliferation and migration of MSCs. Microarray and molecular biological assessment displayed an increased expression and secretion of Ccl2, Ccl3, Ccl4 and Il1b in a dose- and time-dependent manner. These chemokines/cytokines of equivalent concentration to those in conditioned medium exerted an inhibitory effect on MSC proliferation and migration after stimulation for 24 h. Transient elevation of phospho-p38 in MSCs upon AGE-BSA stimulation was blocked with p38 inhibitor.ConclusionsThe study indicates that AGE-BSA induces production of chemokines/cytokines in a dose- and time-dependent manner via activation of ROS-p38 mediated pathway. These chemokines/cytokines exert an inhibitory effect on MSC growth and migration, suggesting an amplified dysfunction of MSCs by AGEs.

Highlights

Advanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs)
advanced glycation end products (AGEs)-BSA induced reactive oxygen species (ROS) accumulation and attenuated proliferation of MSCs Fluorescence-activated cell sorting (FACS) showed that MSCs were negative for CD34 and CD45, and strongly expressed CD29 and CD90
The MTT assay showed that AGE-BSA timeand dose-dependently inhibited proliferation of MSCs, with concentration of 200 ug/ml exhibiting remarkable effects at 24 h (p < 0.05, Figure 1A)

Summary

Introduction

Advanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs). MSCs have a potential role in cell replacement therapy in acute myocardial infarction and ischemic cardiomyopathy. Mechanisms of AGEs on MSCs are still not unveiled. Emerging evidence has demonstrated that cell-based therapy including mesenchymal stem cells (MSCs) for acute myocardial infarction or ischemic cardiomyopathy holds promise [1,2,3]. MSCs, isolated from bone marrow, exhibit a high capacity of ex vivo expansion, allowing further biological modifications and clinically huge-dose preparation of the cells. Type 2 diabetes mellitus (T2DM) decreases the abundance of bone marrow derived CD133+ stem cells following acute myocardial infarction, and limits their activation [9]. The abnormal profiles of MSCs in diabetes and diseaserelated mechanisms have been less clarified

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