Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells.
BACKGROUND
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. However, mechanisms of AGEs on MSCs are still not unveiled.


METHODS
Reactive oxygen species (ROS), genes regulation, cell proliferation and migration have been detected by AGE-BSA stimulated MSCs.


RESULTS
We 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.


CONCLUSIONS
The 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.
Yang
Ke
K
Department of Cardiology, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, P.R. China.
Wang
Xiao Qun
XQ
He
Yu Song
YS
Lu
Lin
L
Chen
Qiu Jing
QJ
Liu
Jing
J
Shen
Wei Feng
WF
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017252:CD3 Complex; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D016207:Cytokines; D017127:Glycation End Products, Advanced; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D048051:p38 Mitogen-Activated Protein Kinases