Abstract
Short-term persistence of transplanted cells during early post-implant period limits clinical efficacy of cell therapy. Poor cell survival is mainly due to the harsh hypoxic microenvironment transplanted cells face at the site of implantation and to anoikis, driven by cell adhesion loss. We evaluated the hypothesis that viral-mediated expression of a gene conferring hypoxia resistance to cells before transplant could enhance survival of grafted cells in early stages after implant. We used adipose tissue as cell source because it consistently provides high yields of adipose-tissue-derived stromal and vascular cells (ASCs), suitable for regenerative purposes. Luciferase positive cells were transduced with lentiviral vectors expressing either green fluorescent protein as control or human manganese superoxide dismutase (SOD2). Cells were then exposed in vitro to hypoxic conditions, mimicking cell transplantation into an ischemic site. Cells overexpressing SOD2 displayed survival rates significantly greater compared to mock transduced cells. Similar results were also obtained in vivo after implantation into syngeneic mice and assessment of cell engraftment by in vivo bioluminescent imaging. Taken together, these findings suggest that ex vivo gene transfer of SOD2 into ASCs before implantation confers a cytoprotective effect leading to improved survival and engraftment rates, therefore enhancing cell therapy regenerative potential.
Highlights
Cell therapy is an innovative approach for the treatment of some acute and chronic degenerative conditions [1]
Adipose tissue-derived stromal and vascular cells were isolated from lipoaspirates obtained from human donors [24]
Immunoblotting using anti-superoxide dismutase 2 (SOD2) antibodies followed by densitometric analysis revealed a 2.5-fold increased expression upon SOD2 gene transfer, compared to mock-transduced ASCs (Figure 1A,B)
Summary
Cell therapy is an innovative approach for the treatment of some acute and chronic degenerative conditions [1]. Transplanted cells may promote tissue regeneration through different mechanisms, including cell differentiation, cell fusion and paracrine effects via the secretion of various cytokines, growth factors and/or microvesicles. Anti-death strategies have been explored to promote the survival of transplanted cells and increase the therapeutic potential of transplantation therapy [9,10,11]. These methods include continuous infusion of trophic factors and hypoxic preconditioning [12]. We provide evidence that ex vivo genetic modification of ASCs by lentiviral-mediated SOD2 gene transfer provides a benefit by promoting cell survival to hypoxia in vitro and by enhancing engraftment in vivo
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