This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/5/754    most recent ATVBAHA.108.174870v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mohri, T. Articles by Azuma, J. Search for Related Content PubMed PubMed Citation Articles by Mohri, T. Articles by Azuma, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Stem Cells

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:754.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Signals Through Glycoprotein 130 Regulate the Endothelial Differentiation of Cardiac Stem Cells

Tomomi Mohri; Yasushi Fujio; Masanori Obana; Tomohiko Iwakura; Koichi Matsuda; Makiko Maeda; Junichi Azuma

From the Department of Clinical Pharmacology and Pharmacogenomics (T.M., Y.F., M.O., T.I., K.M., M.M., J.A.), Graduate School of Pharmaceutical Sciences, Osaka University; and the School of Pharmacy (M.M.), Hyogo University of Health Sciences, Japan.

Correspondence to Yasushi Fujio, Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita City, Osaka, 565-0871, Japan. E-mail fujio{at}phs.osaka-u.ac.jp

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- (TNF-), 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-, 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.

We investigated the molecular mechanisms of cardiac stem cell differentiation. The activation of gp130 by IL-6 family cytokines results in the commitment of Sca-1+ cells to endothelial cell lineage, proposing a novel mechanism for neovascularization. These findings may provide insights into development of regeneration therapies targeting cardiac Sca-1+ cells.

Key Words: cytokines • gp130 • Sca-1 • endothelial cells • neovascularization