title: Interleukin-27 induces the endothelial differentiation in Sca-1+ cardiac resident stem cells.
abstract: Cytokines play important roles in cardiac repair and regeneration. Recently, we demonstrated that interleukin (IL)-6 family cytokines induce the endothelial differentiation of Sca-1+ cardiac resident stem cells through STAT3/Pim-1 signaling pathway. In contrast, the biological functions of IL-12 family cytokines in heart remain to be elucidated, though they show structural homology with IL-6. In the present study, we examined the effects of IL-12 family cytokines on the transdifferentiation of cardiac Sca-1+ cells into cardiac cells. RT-PCR analyses revealed that IL-27 receptor α (IL-27Rα), but not IL-12R or IL-23R, was expressed in cardiac Sca-1+ cells. The transcript expression of IL-27 was elevated in murine hearts in cardiac injury models. Intriguingly, IL-27 stimulation for 14 days induced the endothelial cell (EC) marker genes, such as CD-31 and VE-cadherin. Immunoblot analyses clarified that IL-27 treatment rapidly phosphorylated STAT3. IL-27 upregulated the expression of Pim-1, but the overexpression of dominant negative STAT3 abrogated the induction of Pim-1 by IL-27. Finally, adenoviral transfection of dominant negative Pim-1 inhibited IL-27-induced EC differentiation of cardiac Sca-1+ cells. These findings demonstrated that IL-27 promoted the commitment of cardiac stem cells into the EC lineage, possibly leading to neovascularization as a novel biological function. IL-27 could not only regulate the inflammation but also contribute to the maintenance of the tissue homeostasis through stem cell differentiation at inflammatory sites.
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Obana
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Mohri
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ebara
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Otani
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan. Electronic address: fujio@phs.osaka-u.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D006335:Heart Injuries / Q000473:pathology; D018664:Interleukin-12 / Q000276:immunology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D051573:Proto-Oncogene Proteins c-pim-1 / Q000096:biosynthesis / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D015820:Cadherins; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007378:Interleukins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C528688:interleukin-23 receptor, mouse; D018664:Interleukin-12; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Cardiac stem cells; Endothelial differentiation; Interleukin-27; Signal transduction