Signals through glycoprotein 130 regulate the endothelial differentiation of cardiac stem cells.
OBJECTIVE
Cardiac Sca-1+ cells were originally identified as multipotent stem cells. To address the regulation of their differentiation, we investigated the effects of the proinflammatory cytokines on their endothelial differentiation.


RESULTS
We examined the effects of the proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-11, and cardiotrophin-1 (CT-1) on the cardiac Sca-1+ cell differentiation. IL-11 and CT-1, whose receptor systems use glycoprotein 130 (gp130), induced endothelial-specific genes in Sca-1+ cells, but not TNF-alpha, IL-1beta, or IL-6, analyzed by RT-PCR and by immunocytochemistry. Immnunoblot analyses showed that IL-11 and CT-1 activated signal transducer and activator of transcription 3 (STAT3), a downstream target of gp130, but not other cytokines. Though IL-6 receptor is not endogenously expressed in Sca-1+ cells, IL-6 exhibited the activity to induce the endothelial markers in the presence of soluble IL-6 receptor, an agonistic receptor, associated with STAT3 phosphorylation. Moreover, the inhibition of STAT3, by its dominant-negative form or siRNA, suppressed the induction of endothelial specific genes by IL-11 and CT-1. Finally, LIF and IL-11 transcripts were upregulated in postinfarct myocardium, accompanied by the induction of Sca-1+/VE-cadherin+ cells.


CONCLUSIONS
Gp130/STAT3 pathway plays critical roles in the regulation of endothelial differentiation of cardiac Sca-1+ cells.
Mohri
Tomomi
T
Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
Fujio
Yasushi
Y
Obana
Masanori
M
Iwakura
Tomohiko
T
Matsuda
Koichi
K
Maeda
Makiko
M
Azuma
Junichi
J
D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D015850:Interleukin-6; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*
D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130