Cardiomyocytes overexpressing TNF‐α attract migration of embryonic stem cells via activation of p38 and c‐Jun amino‐terminal kinase

Abstract

Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis of myocardial infarction. Stem cells are able to regenerate infarcted myocardium. This study investigated whether TNF-α 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-α cDNA, were plated in the lower compartments and mouse ESCs tagged with green fluorescent protein were added to the upper compartments. TNF-α level was significantly increased in the medium of the lower compartments seeded with TNF-α-transfected cardiomyocytes. Compared with the controls, overexpression of TNF-α 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-α receptor (TNF-RII), but not by the antibody against the type I TNF-α 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-α-treated ESCs. Inhibition of the activity of p38 or JNK significantly attenuated TNF-α-induced ESC migration. Our data demonstrate that excessive TNF-α stimulates TNF-RII and enhances migration of ESCs in vitro. Activation of p38 and JNK is required for TNF-α-enhanced ESC migration.—Chen, Y., Ke, Q., Yang, Y., Rana, J. S., Tang, J., Morgan, J. P., Xiao, Y.-F. Cardiomyocytes overexpressing TNF-α attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase.