Dynamics of cardiac stem cells in myocardial repair/regeneration and regulation of their cell fate by cytokines

• Project/Area Number: 20390069
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Osaka University
• Principal Investigator: FUJIO Yasushi Osaka University, 大学院・薬学研究科, 教授 (20359839)
• Co-Investigator(Kenkyū-buntansha): AZUMA Junichi 大阪大学, 大学院・薬学研究科, 教授 (30144463) ; MAEDA Makiko 兵庫医療大学, 薬学部, 講師 (70461168)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2009: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 組織幹細胞 / サイトカイン / 心筋リモデリング / 細胞運命 / 心臓 / 心筋組織幹細胞 / 血管内皮 / IL-6 / STAT3 / Pim-1 / 心筋細胞

Research Abstract

So far, cardiac regenerative activity has been believed to be trivial; however, recent studies have demonstrated that pluripotent stem cells exist in myocardium. In this study, we addressed the molecular mechanisms of cardiac stem cell differentiation and examined the cellular dynamics of the cardiac stem cell-derived endothelial cells in infarct myocardium. And we found that IL-6 family cytokines induce endothelial differentiation from cardiac stem cells through STAT3/Pim-1 pathway both in vitro and in vivo.

Research Products

• [Journal Article] STAT3/Pim-1 signaling pathway plays a crucial role in endothelial differentiation of cardiac resident stem cells both in vitro and in vivo. (2011)
  • Author(s): Iwakura T., Mohri T., Hamatani T., Obana M., Yamashita T., Maeda M., Katakami N., Kaneto H., Komuro I., Azuma J., Nakayama H., Fujio Y.
  • Journal Title: J.Mol.Cell.Cardiol. In press
• [Journal Article] SHP2 negatively regulates skeletal alpha-actin gene expression downstream of gp130 signaling in cardiomyocytes. (2010)
  • Author(s): Nakaoka Y., Shioyama W., Kunimoto S., Fujio Y., Higuchi K., Nishida K., Arita, Y., Kuroda T., Hirota H., Yamauchi-Takihara K., Hirano T., Komuro I., Mochizuki N.
  • Journal Title: J.Mol.Cell.Cardiol. 49 Pages: 157-164
• [Journal Article] Therapeutic activation of STAT3 by interleukin-11 ameliorates cardiac fibrosis after myocardial infarction. (2010)
  • Author(s): Obana M., Maeda M., Takeda K., Hayama A., Mohri T., Yamashita T., Nakaoka Y., Komuro I., Takeda K., Matsumiya G., Azuma J., Fujio Y.
  • Journal Title: Circulation. 121 Pages: 684-691
• [Journal Article] IL-11の心血管系における作用 (2010)
  • Author(s): 尾花理徳、前田真貴子、藤尾慈
  • Journal Title: 循環器科 67 Pages: 156-162
• [Journal Article] SHP2 negatively regulates skeletal alpha-actin gene expression downstream of gp130 signaling in cardiomyocytes. (2010)
  • Author(s): Nakaoka, Y., et al
  • Journal Title: J.Mol.Cell.Cardiol. Volume: 49 Pages: 157-164
  • Peer Reviewed
• [Journal Article] RGS2 determines the preventive effects of ARB against vascular remodeling : Toward personalized medicine of ARB in anti-hypertensive therapy. (2010)
  • Author(s): Fujio, Y.
  • Journal Title: Hypertension.Res. Volume: 33 Pages: 1221-1222
  • Peer Reviewed
• [Journal Article] IL-11の心血管系における作用 (2010)
  • Author(s): 尾花理徳, ら
  • Journal Title: 循環器内科 Volume: 67 Pages: 156-162
• [Journal Article] 90. Therapeutic activation of STAT3 by interleukin-11 ameliorates cardiac fibrosis after myocardial infarction. (2010)
  • Author(s): Obana, M.
  • Journal Title: Circulation 121 Pages: 684-691
  • Peer Reviewed
• [Journal Article] Signals through glycoprotein 130 regulate the endothelial differentiation of cardiac stem cells. Arterioscler. (2009)
  • Author(s): Mohri T., Fujio Y., Iwakura T., Matsuda K., Maeda M., Azuma J.
  • Journal Title: Thromb.Vasc.Biol. 29 Pages: 754-760
• [Journal Article] Signals through glycoprotein 130 regulate the endothelial differentiation of cardiac stem cells. (2009)
  • Author(s): Mohri, T., et al/
  • Journal Title: Arterioscler.Thromb.Vasc.Biol. 29 Pages: 757-760
  • Peer Reviewed
• [Journal Article] Involvement of transcriptional factor TonEBP in the regulation of the taurine transporter in the cardiomyocyte. (2009)
  • Author(s): Ito, T., et al.
  • Journal Title: Adv.Exp.Med.Biol. 643 Pages: 523-532
• [Journal Article] Beneficial effect of taurine treatment against doxorubicin-induced cardiotoxicity in mice. (2009)
  • Author(s): Ito, T., et al.
  • Journal Title: Adv.Exp.Med.Biol. 643 Pages: 65-74
• [Journal Article] Clinical significance of plasma endothelin-1 level after bosentan administration in pulmonary artery hynertension. (2009)
  • Author(s): Hiramoto, Y., et al.
  • Journal Title: J.Cardiol. 53 Pages: 374-380
  • Peer Reviewed
• [Journal Article] Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. (2009)
  • Author(s): Ohno M., et al.
  • Journal Title: Eur.J.Clin.Pharmcol. 65 Pages: 1097-1103
  • Peer Reviewed
• [Journal Article] Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38 MAP kinase in cardiac myocytes. (2008)
  • Author(s): Yamamoto, Y., Hoshino, Y., Ito, T., Nariai, T., Mohri, T., Obana M., Hayata, N., Uozumi, Y., Maeda M., Fujio Y., Azuma, J.
  • Journal Title: Cardiovasc.Res. 79 Pages: 89-96
• [Journal Article] Interaction of scaffolding adaptor protein Gabl with tyrosine phosphataseSHP2 negatively regulates IGF-I-dependent myogenic differentiation viaERK1/2 signaling pathway. (2008)
  • Author(s): Koyama, T., et al
  • Journal Title: J. Biol. Chem. 283 Pages: 24234-24244
  • Peer Reviewed
• [Journal Article] Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38MAP kinase in cardiac myocytes (2008)
  • Author(s): Yamamoto, Y., et al
  • Journal Title: Cardiovasc. Res. 79 Pages: 89-96
  • Peer Reviewed
• [Journal Article] Connective tissue growth factor induces cardiac hypertrophy through Akt signaling. (2008)
  • Author(s): Hayata, N., et al
  • Journal Title: Biochem. Biophys. Res. Commun. 370 Pages: 274-278
  • Peer Reviewed
• [Journal Article] Taurine depletion caused by knocking out the taurine transportergene leads to cardiomyopathy with cardiac atrophy. (2008)
  • Author(s): Ito T., et al
  • Journal Title: J. Mol. Cell. Cardiol. 44 Pages: 927-937
  • Peer Reviewed
• [Journal Article] Polymorphisms of norepinephrine transporter and adrenergic receptor α_(1D) are associated with the response to β-blockers in dilated cardiomyopathy. (2008)
  • Author(s): Nonen, S., et al
  • Journal Title: Pharmacogenomics J. 8 Pages: 78-84
  • Peer Reviewed
• [Journal Article] Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-Met signaling
  • Author(s): Shioyama, W., et al
  • Journal Title: Circ.Res. Volume: (In press)
  • Peer Reviewed
• [Journal Article] SHP2 negatively regulates skeletal alpha-actin gene expression downstream of gp130 signaling in cardiomyocytes.
  • Author(s): Nakaoka, Y.
  • Journal Title: J.Mol.Cell.Cardiol. (In press)
  • Peer Reviewed
• [Journal Article] Signals through glycoprotein 130 regulate the endothelial differentiation ofcardiac stem cells.
  • Author(s): Mohri, M., et al
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. in press
  • Peer Reviewed
• [Presentation] Interleukin-11 exhibits the post-conditioning effects against ischemia reperfusion injury through cardiac STAT3 activation (2011)
  • Author(s): Obana, M., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-24
• [Presentation] Disruption of leptin signal exacerbates myocardial injury by enhancing ER stress after myocardial infarction (2011)
  • Author(s): Shiragaki, M., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-24
• [Presentation] Interleukin-6 family cytokines induce endothelial-cell differentiation of cardiac Sca-1+ cells via STAT3/Pim-1 signaling pathway (2011)
  • Author(s): Iwakura, T., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-23
• [Presentation] PTP1B negative regulates JAK/STAT cardioprotective signaling in cardiomyocytes (2011)
  • Author(s): Murasawa, S., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-23
• [Presentation] Th17 cells are indispensable for myocardial inflammation in autoimmune myocarditis (2011)
  • Author(s): Yamashita, T., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-23
• [Presentation] Cathelicidin antimicrobial peptide (CAMP) is induced in autoimmune myocarditis and reduces the motility of cardiac fibroblasts (2011)
  • Author(s): Matsui, K., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-23
• [Presentation] Olmesartan attenuates angiotensin II induced interleukin-23 production in cardiac fibroblasts (2011)
  • Author(s): Katayama, K., et al
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-23
• [Presentation] Pim-1 kinase is required for endothelial differentiation of cardiac stem cells via STAT3 signaling pathway (2010)
  • Author(s): Iwakura, T., et al
  • Organizer: American Heart Association Scientific Sessions 2010
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 2010-11-16
• [Presentation] IL-11 ameliorates cardiac remodeling after myocardial infarction via STAT3 pathway activation in cardiomyocytes. (2010)
  • Author(s): 尾花理徳, 他
  • Organizer: 日本循環器学会
  • Place of Presentation: 京都市
  • Year and Date: 2010-03-05
• [Presentation] Interleukin-11 Attenuates Infarct Size And Improves Ventricular Function In a Canine Heart Model Of Ischemia/Reperfusion Injury (2009)
  • Author(s): Koji Takeda, 他
  • Organizer: American Heart Association
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2009-11-15
• [Presentation] Glycoprotein 130/signal transducer and activator of transcription 3 pathway regulates the differentiation of cardiac Sea-1+ cells into endothelial cells (2009)
  • Author(s): 毛利友美, 他
  • Organizer: 第32回心筋代謝研究会
  • Place of Presentation: 吹田市
  • Year and Date: 2009-07-04
• [Presentation] 心筋梗塞後心筋における組織幹細胞由来血管内皮細胞の同定 (2009)
  • Author(s): 松田浩一, 他
  • Organizer: 第82回日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-18
• [Presentation] Thl7細胞は心筋梗塞後慢性炎症期に誘導される (2009)
  • Author(s): 端山明子, 他
  • Organizer: 第82回日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-18
• [Presentation] Thl7細胞の心筋浸潤は心筋炎の重症度と相関する (2009)
  • Author(s): 山下朋美, 他
  • Organizer: 第82回日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-18
• [Presentation] 心筋細胞においてIL-10はgpl30シグナルによるSTAT3、ERKl/2の活性化を介して誘導される (2009)
  • Author(s): 岩倉智彦, 他
  • Organizer: 第82回日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-16
• [Presentation] Drug Dosing Considerations for Antithrombotic Therapy (2009)
  • Author(s): Fujio, Y.
  • Organizer: Session : Joint AHA/Asian Pacific Society of Cardiology : Pharmacogenomics : Implications for Drug Dosing and Clinical Trials in Different Populations. American Heart Association, Scientific Session 2009
  • Place of Presentation: Orlando
• [Presentation] Cytokine (2008)
  • Author(s): Fujio, Y.
  • Organizer: American Heart AssociationScientific Session
  • Place of Presentation: New Orleans
  • Year and Date: 2008-11-11
• [Presentation] Cytokine Session : How to Recognize Cell Death and Its Impact on Heart Failure American Heart Association (2008)
  • Author(s): Fujio, Y.
  • Organizer: Scientific Session 2008
  • Place of Presentation: New Orleans