Cardiomyocytes overexpressing TNF-alpha attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase.
Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the pathogenesis of myocardial infarction. Stem cells are able to regenerate infarcted myocardium. This study investigated whether TNF-alpha was able to induce migration of embryonic stem cells (ESCs) in vitro. We used a Transwell assay in which neonatal rat cardiomyocytes, with or without transfection of TNF-alpha cDNA, were plated in the lower compartments and mouse ESCs tagged with green fluorescent protein were added to the upper compartments. TNF-alpha level was significantly increased in the medium of the lower compartments seeded with TNF-alpha-transfected cardiomyocytes. Compared with the controls, overexpression of TNF-alpha significantly enhanced migration of ESCs to the lower compartments. This enhancement was attenuated by preincubation of ESCs with the antibody against the type II TNF-alpha receptor (TNF-RII), but not by the antibody against the type I TNF-alpha receptor (TNF-RI). Western blot analysis showed that the phosphorylated protein levels of p38 and c-Jun amino-terminal kinase (JNK) were significantly increased in TNF-alpha-treated ESCs. Inhibition of the activity of p38 or JNK significantly attenuated TNF-alpha-induced ESC migration. Our data demonstrate that excessive TNF-alpha stimulates TNF-RII and enhances migration of ESCs in vitro. Activation of p38 and JNK is required for TNF-alpha-enhanced ESC migration.
Chen
Yu
Y
Stem Cells Research Laboratory, The Charles A. Dana Research Institute and Harvard-Thorndike Laboratory, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Ke
Qingen
Q
Yang
Yinke
Y
Rana
Jamal S
JS
Tang
Jian
J
Morgan
James P
JP
Xiao
Yong-Fu
YF
D000818:Animals; D002450:Cell Communication; D002465:Cell Movement; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology*; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013234:Stem Cells / Q000201:enzymology / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases