RGD Reference Report - Mesenchymal stem cell-based gene therapy with prostacyclin synthase enhanced neovascularization in hindlimb ischemia. - Rat Genome Database

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

Authors: Ishii, Masakazu  Numaguchi, Yasushi  Okumura, Kenji  Kubota, Ryuji  Ma, Xiuyang  Murakami, Ryuichiro  Naruse, Keiji  Murohara, Toyoaki 
Citation: Ishii M, etal., Atherosclerosis. 2009 Sep;206(1):109-18. doi: 10.1016/j.atherosclerosis.2009.02.023. Epub 2009 Mar 11.
RGD ID: 401960096
Pubmed: PMID:19344900   (View Abstract at PubMed)
DOI: DOI:10.1016/j.atherosclerosis.2009.02.023   (Journal Full-text)


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 (PGI(2)), to examine whether it could enhance engraftment and neovascularization in hindlimb ischemia.
METHODS AND RESULTS: We engineered the overexpression of PGI(2) 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 delta, 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 PGI(2) 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanlimb ischemia treatmentISOPtgis (Rattus norvegicus)rat gene in human cells in a mouse modelRGD 
PtgisRatlimb ischemia treatmentIMP rat gene in human cells in a mouse modelRGD 
PtgisMouselimb ischemia treatmentISOPtgis (Rattus norvegicus)rat gene in human cells in a mouse modelRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PtgisRatcellular response to hypoxia  IMP  RGD 
PtgisRatpositive regulation of gene expression  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptgis  (prostaglandin I2 synthase)

Genes (Mus musculus)
Ptgis  (prostaglandin I2 (prostacyclin) synthase)

Genes (Homo sapiens)
PTGIS  (prostaglandin I2 synthase)


Additional Information