Abstract
Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Poor survival and vascular engraftment rates of transplanted cells force them to work mainly via time-limited paracrine actions. Although several approaches, including the use of soluble vascular endothelial growth factor (sVEGF)—VEGF165, have been developed in the last 10 years to enhance cell survival, they showed limited efficacy. Here, we report a pro-survival approach based on VEGF-immobilized microparticles (VEGF-MPs). VEGF-MPs prolong VEGFR-2 and Akt phosphorylation in cord blood-derived late outgrowth endothelial progenitor cells (OEPCs). In vivo, OEPC aggregates containing VEGF-MPs show higher survival than those treated with sVEGF. Additionally, VEGF-MPs decrease miR-17 expression in OEPCs, thus increasing the expression of its target genes CDKN1A and ZNF652. The therapeutic effect of OEPCs is improved in vivo by inhibiting miR-17. Overall, our data show an experimental approach to improve therapeutic efficacy of proangiogenic cells for the treatment of ischemic diseases.
Highlights
Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases
We further show that the prolonged VEGFR-2 phosphorylation in cell aggregates containing VEGF-MPs is associated with the down-regulation of miR-17 and increase in the expression of its target genes CDKN1A and ZNF652
After demonstrating the bioactivity of immobilized VEGF by phosphorylation of VEGFR-2 and induction of the intracellular accumulation of Ca2+, we showed that immobilized VEGF enhanced the survival of outgrowth endothelial progenitor cells (OEPCs) both in vitro and in vivo
Summary
Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Some approaches have been explored to augment cell survival in ischemic conditions These include the exposure of transplanted cells to temperature shock, genetic modification of cells to overexpress growth factors and/or anti-apoptotic proteins and pre-conditioning the cells with pharmacological agents and cytokines[7, 8]. Most of these methodologies have not reached the clinical trials, because they have shown limited effectiveness due to the multi-factorial nature of cell death. Due to the prolonged VEGFR-2 phosphorylation and higher activation of subsequent pathways, immobilized VEGF might be a promising pro-survival agent for cell-based therapies. We further show that the prolonged VEGFR-2 phosphorylation in cell aggregates containing VEGF-MPs is associated with the down-regulation of miR-17 and increase in the expression of its target genes CDKN1A and ZNF652
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