240
Mesenchymal stem cells transfected with minicircle-HIF-1a decreases LV adverse remodelling via release of cardioprotective miRNAs and pro-angiogenic factors

Extract

Background: Mesenchymal stem cell (MSC) therapy for treatment of acute and chronic ischemic heart failure has shown promising results in preclinical and early clinical trials, despite challenges in delivery root, number of implanted cells and cell retention rate. Beneficial effects were mainly observed via the rich paracrine effects of MSCs. Hypoxia-inducible factor-1α (HIF1α), which is one of the most powerful anti-ischemic factors, may modulate angiogenic and regenerative substances in vivo.

Purpose: To enhance the paracrine anti-ischemic and anti-remodelling efficacy of the cell therapy, porcine allogeneic MSCs were transfected with virus-free minicircle plasmid driving HIF1α transgene (MSC-MiCi-HIF1α).

Methods: Domestic male pigs (n=16) underwent closed-chest reperfused acute myocardial infarction (MI) via balloon-occlusion of the mid-LAD for 90 minutes, followed by reperfusion. One month later the animals were randomized to receive either MSCs alone (n=6) or MSC-MiCi-HIF1α (n=10) (15±3 x10^6 cells). Cells were injected into the border zone of infarction by 3D guided NOGA electro-anatomical mapping system. Sequential HIF1α expression and early angiogenesis were investigated at 3, 12, and 24h follow-up (FUP) by harvesting animals of the MSC-MiCi-HIF1α group. Magnetic resonance imaging with late enhancement was performed in the surviving 6 animals of each group. Angiogenesis proteome profiling and RT-PCR quantified mRNA (Angiopoietin-2, VEGF-A, CD31 and apelin) and miRNA (miR-1, miR-24, miR132) expressions. Immunohistology sections were stained with anti-caspase-3 antibody and apoptosis rate was quantified.