Cyclosporin A pre‐incubation attenuates hypoxia/reoxygenation‐induced apoptosis in mesenchymal stem cells

Abstract

Although mesenchymal stem cells (MSCs) are being tested for cardiac repair, the majority of transplanted cells undergo apoptosis in the ischaemic heart because of the effects of ischaemia/reperfusion, poor blood supply and other pro-apoptotic factors. Several experimental and clinical studies have suggested that cyclosporin A (CsA) treatment reduces apoptosis in human endothelial cells and neurocytes. However, the effect of CsA on the apoptosis in MSCs is still unclear. In this study, we investigated whether CsA could inhibit hypoxia/ reoxygenation (H/R)-induced apoptosis in MSCs. MSCs pre-incubated with or without CsA were subjected to 6 h of hypoxia followed by 12 h of reoxygenation. Our data showed that pre-incubation with 0.5-5 microM CsA dose-dependently protected the MSCs from H/R injury, as evidenced by decreased apoptosis and increased cell viability. CsA inhibited the H/R-induced translocation of cytochrome c, increased bcl-2 expression and restored mitochondrial membrane potential. CsA also increased the expression of p-BAD. We propose that preincubation MSCs with CsA inhibits MSC apoptosis through the mitochondrial and BAD pathway.

Protective paracrine effect of mesenchymal stem cells on cardiomyocytes

“…Mitochondrial transmembrane potential was assessed using the lipophilic cationic probe JC-1 (BioVision, USA), a sensitive fluorescent dye, as we had described before (Chen et al, 2008). Red emission from the dye is attributed to a potentialdependent aggregation in the mitochondria.…”

Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways

“…It has also been demonstrated that preconditioning MSCs with stromal-derived factor 1α (SDF-1α) alone or in combination with growth factors such as fibroblast growth factor-2, insulin-like growth factor-1, and bone morphogenetic protein-2 can alleviate the host cell apoptosis and enhance their therapeutic effects (Mias et al, 2008). Our previous studies have shown that some candidates for preconditioning, such as heregulin (Mias et al, 2008), cyclosporin A (Chen et al, 2008), angiopoietin-1 (Liu et al, 2008), and dimethyloxalylglycine (DMOG) (Liu et al, 2009b), can protect MSCs against hypoxia and serum deprivation-induced apoptosis through classic cytoplasmic and/or mitochondrial apoptotic pathways.…”

Cyclosporin in Cell Therapy for Cardiac Regeneration

“…In several experiments, stem cells were incubated with varying concentrations of CsA and proliferation [47–57], survival [49], apoptosis [58, 59], differentiation [53, 55, 57], migration [53], and angiogenesis [59] were analysed. Table 1 summarizes the studies that revealed a positive effect (enhanced differentiation, proliferation, survival, or decreased apoptosis) or negative impact (reduced differentiation, proliferation, survival, or increased apoptosis) of CsA on different cell types, compared to control.…”

“…Reduced apoptosis and increased survival, as seen in Chen et al and Hunt et al, are explained by prevention of mitochondrial dysfunction [49, 58] and promotion of bcl-2, an antiapoptotic factor [58]. However, Hunt et al showed decreased cell viability and decreased cell proliferation at higher concentrations (≥5 µg/mL) [49].…”

“…Two studies showed reduced proliferation [54, 55], one study showed no effect on proliferation [52], and only one study showed a positive effect in the form of reduced MSC apoptosis [58]. Two studies used embryonic stem cells (ESCs) [51, 56], and both revealed a positive pro-proliferative effect of CsA, suggesting ESCs may benefit from the presence of CsA.…”