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Arterioscler Thromb Vasc Biol. 2009 May;29(5):754-60. doi: 10.1161/ATVBAHA.108.174870. Epub 2009 Feb 12.

Signals through glycoprotein 130 regulate the endothelial differentiation of cardiac stem cells.

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  • 1Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.

Abstract

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.

METHODS AND 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.

PMID:
19213943
[PubMed - indexed for MEDLINE]
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