Investigation of the molecular mechanism of progenitor cell-mediated therapeutic angiogenesis

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 18390232
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Nagoya University
• Principal Investigator: MUROHARA Toyoaki Nagoya University, Graduate School of Medicine, Professor (90299503)
• Co-Investigator(Kenkyū-buntansha): KOMORI Kimihiro Nagoya University, Graduate School of Medicine, Professor (40225587) ; NUMAGUCHI Yasushi Nagoya University, School of Medicine, Associate Professor (90378224) ; SHINTANI Satoshi Nagoya University, University Hospital, Assistant Professor (20309777)
• Project Period (FY): 2006 – 2007
• Keywords: regenerative medicine / angiogenesis / cell therapy / gene therapy / endothelial cell / stem cell / therapeutic angiogenesis / endothelial progenitor cell

Research Abstract

Therapeutic angiogenesis using antologous stem/progenitor cells represents a novel strategy for severely ischemic diseases. Recent reports indicated that adipose tissues could supply adipose-derived stem cells (ASCs). Accordingly, we examined whether implantation of ASCs would augment angiogenesis using a mouse model of hind limb ischemia. C57BL/6J mouse inguinal fat pad was obtained and ASCs were isolated using standard medium.
Fluorescence-activated cell sorter (FACS) analysis revealed that ASCs were Sca-1^+CD31-CD34-flk-1-c-kif-Lin. ASCs expressed vascular endothelial growth factor (VEGF) and stromal cell-derived factor I (SDF-1) mRNAs and proteins. Hind limb ischemia was surgically induced and culture-expanded ASCs(1.0xl0^6cells/animal), PBS or differentiated mature adipocytes(MAs) as control cells were injected into the ischemic tissues. At 3 weeks, the ASC group had a greater laser Doppler blood flow index (0.93±0.08 vs. 0.79±0.14 p<0.05) and a higher capillary density (1.51±0.08 vs. 1.13±0.07 p<0.01) compared to the control group. Implantation ofASCs increased circulating EPCs measured by FACS and culture assay. SDF-I mRNA abundance at ischemic tissues and serum SDF-1 levels were greater in the ASC group than control group. Finally, intraperitoneal injection of an anti-SDF-1 neutralizing antibody reduced therapeutic efficacies of ASCs implantation.
Adipose tissue would be a valuable source for cell-based therapeutic angiogenesis. Moreover, SDF-1 may play a pivotal role in the ASCs-mediated angiogenesis at least in part by facilitating mobilization of EPCs.

Research Products

• [Journal Article] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. (2008)
  • Author(s): Kitamura T, Asai N, Enomoto A, Maeda K, Kato T, Ishida M, Jiang P, Watanabe T, Usuknra J, Kondo T, Costantini F, Murohara T, Takahashi M.
  • Journal Title: Nat. Cell Biol. (in press)(印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin (2008)
  • Author(s): Kitamura, T, Asai, N, Enomoto, A, Maeda, K, Kato, T, Ishida, M, Jiang, P, Watanabe, T, Usukura, J, Kondo, T, Costantini, F, Murohara, T, Takahashi, M
  • Journal Title: Nat. Cell Biol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Therapeutic angiogenesis using novel vascular endothelial growth factor-E/human placental growth factor chimera genes. (2007)
  • Author(s): Inoue N, Kondo T, Kobayashi K, Aoki M, Numaguchi Y, Shibuya M, Murohara T.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. 27 Pages: 99-105
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle-like Progenitor Cells. (2007)
  • Author(s): Yamada T, Kondo T, Numaguchi Y, Tsuzuki M, Matsubara T, Manabe I, Sata M, Nagai R, Murobara T.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. 27 Pages: 2363-2369
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Therapeutic angiogenesis using novel vascular endothelial growth factor-E/human placental growth factor chimera genes (2007)
  • Author(s): Inoue, N, Kondo, T, Kobayashi, K, Aoki, M, Numaguchi, Y, Shibuya, M, Murohara, T
  • Journal Title: Arterioscler. Thromb. Vasa Biol 27 Pages: 99-105
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle-like Progenitor Cells (2007)
  • Author(s): Yamada, T, Kondo, T, Numaguchi, Y, Tsuzuki, M, Matsubara, T, Manabe, I, Sata, M, Nagai, R, Murohara, T
  • Journal Title: Arterioscler. Thromb. Vase. Biol 27 Pages: 2363-2369
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. (2007)
  • Author(s): Kitamura T, Asai N, Enomoto A, Maeda K, Murohara T, Takahashi M.
  • Organizer: American Heart Association, 2007
  • Place of Presentation: Orlando, USA
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin (2007)
  • Author(s): Kitamura, T, Asai, N, Enomoto, A, Maeda, K, Murohara, T, Takahashi, M. Regulation
  • Organizer: American Heart Association 2007
  • Place of Presentation: Orlando, USA
  • Year and Date: 2007-11-06
  • Description: 「研究成果報告書概要(欧文)」より