Mesenchymal stem cell-based gene therapy with prostacyclin synthase enhanced neovascularization in hindlimb ischemia

Masakazu Ishii, Yasushi Numaguchi, Kenji Okumura, Ryuji Kubota, Xiuyang Ma, Ryuichiro Murakami, Keiji Naruse, Toyoaki Murohara

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Objective: Bone marrow cell therapy contributes to collateral formation through the secretion of angiogenic factors by progenitor cells and muscle cells per se, thereby presenting a novel option for patients with critical limb ischemia. However, some cases are refractory to this therapy due to graft failure. Therefore, we used genetic modification of mesenchymal stem cells (MSCs) to overexpress a vasoregulatory protein, prostacyclin (PGI2), to examine whether it could enhance engraftment and neovascularization in hindlimb ischemia. Methods and results: We engineered the overexpression of PGI2 synthase (PGIS) within MSCs, which resulted in higher expression levels of phosphorylated Akt and Bcl-2 than in control. Under hypoxic conditions, the overexpression of PGIS led to upregulated expression of cyclooxigenase-2 and peroxisome proliferator-activated receptor δ, following a 40% increased rate of proliferation in MSCs. We then produced unilateral hindlimb ischemia in C57BL6/J mice, which were injected either with MSCs transfected with GFP, with MSCs overexpressing PGIS, or with vehicle. Laser Doppler analyses demonstrated that the administration of MSCs effectively recovered blood perfusion, and that the peak blood flow was reached within 7 days of surgery in mice with MSCs overexpressing PGIS, which was earlier than that in mice with MSCs transfected with GFP. This beneficial effect was correlated to enhanced collateral formation and muscle bundle proliferation. Conclusion: Sustained release of PGI2 enhanced the proangiogenic function of MSCs and subsequent muscle cell regrowth in the ischemic tissue suggesting potential therapeutic benefits of cell-based gene therapy for critical limb ischemia.

Original languageEnglish
Pages (from-to)109-118
Number of pages10
JournalAtherosclerosis
Volume206
Issue number1
DOIs
Publication statusPublished - Sep 2009

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Keywords

  • Angiogenesis
  • Cell therapy
  • Hindlimb ischemia
  • Mesenchymal stem cell
  • Prostacyclin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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