Development of new cardiovascular regeneration therapy by regulating apoptosis and bone marrow stem cell mobilization

• Project/Area Number: 16590667
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Shinshu University
• Principal Investigator: TAKAHASHI Masafumi Shinshu University, Department of Organ Regeneration, Associate Professor, 大学院医学系研究科, 助教授 (40296108)
• Co-Investigator(Kenkyū-buntansha): ISE Hirohiko Shinshu University, Department of Organ Regeneration, Assistant professor, 大学院医学系研究科, 助手 (10324253) ; IKEDA Uichi Shinshu University, Department of Organ Regeneration, Professor, 大学院医学系研究科, 教授 (30221063)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: cytokine / atherosclerosis / myocardial infarction / myocarditis / regeneration / bone marrow / angiogenesis / 骨髄幹細胞 / 血管内皮前駆細胞 / 血管平滑筋細胞 / マウス / アポトーシス / 心筋細胞

Research Abstract

We have previously reported the effectiveness and safety of therapeutic angiogenesis by transplantation of autologous bone marrow cells to ischemic limbs ; however, this therapy needs general anesthesia to obtain bone marrow cells. To develop more efficient therapy using bone marrow cells, we examined the effect of several factors, such as G-CSF, M-CSF, and erythropoietin (EPO), that regulate apoptosis and bone marrow cell mobilization in rat and murine models of cardiovascular diseases. The major findings of this study are : (1) G-CSF mobilized endothelial progenitor cells, accelerated reendothelialization, and decreased neointimal formation after vascular injury ; (2) M-CSF induced neointimal formation in the early stages after vascular injury through activation of SDF-1/CXCR4 system ; (3) EPO attenuated inflammatory cell infiltration and cytokine expression, and it improved cardiac function and reduced cardiac inflammation in autoimmune myocarditis. These findings suggest the therapeutic potential of these factors in cardiovascular diseases.

Research Products

• [Journal Article] M-CSF accelerates neointimal formation in the early phase after vascular injury in mice : the critical role of the SDF-1-CXCR4 system. (2007)
  • Author(s): Shiba Y, Takahashi M, Yoshioka T, Yajima N, Morimoto H, Izawa A, Ise H, Hatake K, Motoyoshi K, Ikeda U
  • Journal Title: Arterioscler Thromb Vase Biol 27 Pages: 283-289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Erythropoietin attenuates the development of experimental autoimmune myocarditis. (2007)
  • Author(s): Hirose S, Takahashi M, Ogawa R, Morimoto H, Izawa A, Sato H, Ise H, Hongo M, Ikeda U
  • Journal Title: Cardiovasc Drugs Ther 21 Pages: 17-27
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] M-CSF accelerates neointimal formation in the early phase after vascular injury in mice : the critical role of the SDF-1-CXCR4 system. (2007)
  • Author(s): Shiba Y, Takahashi M, Yoshioka T, Yajima N, Morimoto H, Izawa A, Ise H, Hatake K, Motoyoshi K, Ikeda U.
  • Journal Title: Arterioscler Thromb Vasc Biol 27 Pages: 283-289
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Erythropoietin attenuates the development of experimental autoimmune myocarditis. (2007)
  • Author(s): Hirose S, Takahashi M, Ogawa R, Morimoto H, Izawa A, Sato H, Ise H, Hongo M, Ikeda U.
  • Journal Title: Cardiovasc Drugs Ther 21 Pages: 17-27
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Erythropoietin attenuates the development of experimental autoimmune myocarditis. (2007)
  • Author(s): Hirose S, Takahashi M, Ogawa R, Morimoto H, Izawa A, Sato H, Ise H, Hongo M, Ikeda U.
  • Journal Title: Cardiovase Drugs Ther 21 Pages: 17-27
• [Journal Article] Cardiac overexpression of MCP-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. (2006)
  • Author(s): Morimoto H, Takahashi M, Izawa A, Ise H, Hongo M, Kolattukudy PK, Ikeda U
  • Journal Title: Circ Res 99 Pages: 891-899
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] G-CSF accelerates reendothelialization and reduces neointimal formation after vascular injury in mice. (2006)
  • Author(s): Yoshioka T, Takahashi M, Shiba Y, Suzuki C, Morimoto H, Izawa A, Ise H, Ikeda U
  • Journal Title: Cardiovasc Res 70 Pages: 61-69
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapeutic potential of endothelial progenitor cells for cardiovascular diseases. (2006)
  • Author(s): Jia L, Takahashi M, Yoshioka T, Morimoto H, Ise H, Ikeda U
  • Journal Title: Current Vascular Pharmacology 4 Pages: 59-65
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Collagen synthesis is required for ascorbic acid-enhanced differentiation of mouse embryonic stem cells into cardiomyocytes. (2006)
  • Author(s): Sato H, Takahashi M, Ise H, Yamada A, Hirose S, Tagawa Y, Morimoto H, Izawa A, Ikeda U
  • Journal Title: Biochem Biophys Res Commun 342 Pages: 107-112
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cardiac overexpression of MCP-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. (2006)
  • Author(s): Morimoto H, Takahashi M, Izawa A, Ise H, Hongo M, Kolattukudy PK, Ikeda U.
  • Journal Title: Circ Res 99 Pages: 891-899
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] G-CSF accelerates reendothelialization and reduces neointimal formation after vascular injury in mice. (2006)
  • Author(s): Yoshioka T, Takahashi M, Shiba Y, Suzuki C, Morimoto H, Izawa A, Ise H, Ikeda U.
  • Journal Title: Cardiovasc Res 70 Pages: 61-69
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Therapeutic potential of endothelial progenitor cells for cardiovascular diseases. (2006)
  • Author(s): Jia L, Takahashi M, Yoshioka T, Morimoto H, Ise H, Ikeda U.
  • Journal Title: Current Vascular Pharmacology 4 Pages: 59-65
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Collagen synthesis is required for ascorbic acid-enhanced differentiation of mouse embryonic stem cells into cardiomyocytes. (2006)
  • Author(s): Sato H, Takahashi M, Ise H, Yamada A, Hirose S, Tagawa Y, Morimoto H, Izawa A, Ikeda U.
  • Journal Title: Biochem Biophys Res Commun 342 Pages: 107-112
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Granulocyte colony-stimulating factor accelerates reendothelialization and reduces neointimal formation after vascular injury in mice. (2006)
  • Author(s): Yoshioka T, Takahashi M, Shiba Y, Suzuki C, Morimoto H, Izawa A, Ise H, Ikeda U.
  • Journal Title: Cardiovasc Res 70 Pages: 61-69
• [Journal Article] Efficacy of mycophenolic acid combined with a novel immunomodulator KRP-203 in rat heart transplantation models. (2006)
  • Author(s): Suzuki C, Takahashi M, Morimoto H, Izawa A, Ise H, Fujishiro J, Murakami T, Ishiyama J, Nakada A, Nakayama J, Ikeda U, Kobayashi E.
  • Journal Title: J Heart Lung Transpl 25 Pages: 302-309
• [Journal Article] Changes in cardiac lipid metabolism during sepsis : the essential role of very low-density lipoprotein receptors. (2006)
  • Author(s): Jia L, Takahashi M, Morimoto H, Takahashi S, Izawa A, Ise H, Iwasaki T, Hattori H, K-J. Wu, Ikeda U.
  • Journal Title: Cardiovasc Res 69 Pages: 545-555
• [Journal Article] Mycophenolate mofetil prevents the development of experimental autoimmune myocarditis. (2005)
  • Author(s): Kamiyoshi Y, Takahashi M, Yokoseki O, Yazaki Y, Hirose S, Morimoto H, Watanabe N, Kinoshita O, Hongo M, Ikeda U.
  • Journal Title: J Mot Cell Cardiol 39 Pages: 467-477
• [Journal Article] A novel immunomodulator KRP-203 combined with cyclosporine A prolonged graft survival and abrogates transplant vasculopathy in rat heart allografts. (2005)
  • Author(s): Takahashi M, Shimizu H, Murakami T, Enosawa S, Suzuki C, Takeno Y, Hakamata Y, Kudou S, Izawa S, Yasue T., Kobayashi E.
  • Journal Title: Transplant Proc 37 Pages: 143-145
• [Journal Article] Interleukin-1beta attenuates uptake of β-very low-density lipoprotein through downregulation of its receptor in vascular smooth muscle cells. (2005)
  • Author(s): Takahashi M, Takahashi S, Suzuki C, Jia L, Morimoto H, Ise H, Iwasaki T, Hattori H, Zenimaru Y, Suzuki J, Miyamori I, Kobayashi E, Ikeda U.
  • Journal Title: J Mol Cell Cardiol 38 Pages: 637-646
• [Journal Article] KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts. (2005)
  • Author(s): H.Shimizu, M.Takahashi, et al.
  • Journal Title: Circulation 111 Pages: 222-229
• [Journal Article] Can a bone marrow cell contribute to organ regeneration? In vivo analysis using transgenic rats with reporter genes (2005)
  • Author(s): Y.Sato, K.M.Takahashi, et al.
  • Journal Title: Transplant Proc 37 Pages: 273-275
• [Journal Article] Development of new inbred transgenic strains of rats with LacZ or GFP. (2005)
  • Author(s): H.Inoue, M.Takahashi, et al.
  • Journal Title: Biochem Biophys Res Commun 329 Pages: 329-329
• [Journal Article] Bone marrow cells differentiate into wound myofibroblasts and accelerate the healing of wounds with exposed bones when combined with an occlusive dressing. (2005)
  • Author(s): Y.Yamaguchi, M.Takahashi, et al.
  • Journal Title: Brit J Dermatol (in press)
• [Journal Article] Interleukin-1beta attenuates uptake of beta-very low-density lipoprotein through downregulation of its receptor in vascular smooth muscle cells. (2005)
  • Author(s): M.Takahashi, S.Takahashi, et al.
  • Journal Title: J Mol Cell Cardiol 38 Pages: 637-646
• [Journal Article] Increase in circulating endothelial progenitor cells after aortic aneurysm repair. (2004)
  • Author(s): T.Eizawa, M.Takahashi, et al.
  • Journal Title: Heart Vessels 19 Pages: 107-110
• [Journal Article] Therapeutic potential of endothelial progenitor cells for ischemic cardiovascular diseases. (2004)
  • Author(s): T.Yoshioka, M.Takahashi, et al.
  • Journal Title: Recent Res Devl Physiol 2 Pages: 283-294
• [Book] Annual Review 循環器 (2006)
  • Author(s): 鈴木智裕, 高橋将文, 吉岡 徹, 池田宇一
  • Publisher: 中外医学社