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

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-α (TNF-α), interleukin (IL)-1β, 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-α, IL-1β, 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. © 2009 American Heart Association, Inc.