You are hereOctober 25, 2013 | Neural Stem Cells
Analyses of Immunosuppressants Effect on NSCs Therapeutic Function
Stem cell therapy in humans currently relies on the use of immunosuppressants to ensure long-term cell survival and function. Commonly used immunosuppressants include Cyclosporine A (CsA), tacrolimus (FK506) and sirolimus (rapamycin); all of which have been shown to have some effect on pathways present in neural cells (Aramburu et al and Hoeffer et al). Researchers from the groups of Uchida et al)Cummings et aland Salazar et al
High and low levels of the immunosuppressants were initially tested in vitro for their effects on βTub+ (neurons) and a decrease in GFAP+ (astroglia) cells, while rapamycin treatment led to an increase in βTub+ and GFAP+ cells. Furthermore, high-dose CsA, low-dose rapamycin and high-dose rapamycin treatment led to reduced cell number suggesting a toxic/anti-proliferative effect. However, no effect on cytotoxicity or apoptotic/necrotic cell death was observed at 24 hours or 7 days, although EdU-detection assays did find a decrease in proliferation for high doses of CsA, low and high doses of rapamycin, but no change with FK506. The final piece of in vitro analysis found that immunosuppressants did not exert a chemoattractant/chemorepellent effects and therefore did not affect
In vivo analysis was carried out through the examination of transplanted hCNS-SCns 9 days in NOD-scid mice after a moderate contusion spinal cord injury. Interestingly, engraftment, proliferation and cell fate were not altered by the addition of immunosuppressants compared to an untreated control. Further stereological quantification analyses also found that the distribution and migration of hCNS-SCns was unaltered.Finally, the researchers investigated functional recovery mediated by hCNS-SCns in the presence of FK506 and anti-CD4 antibody to deplete T-cells and allow for meaningful graft survival (Yan et al). Moderate contusion spinal cord injury was followed by cell transplantation during the chronic phase of the injury (60 days post injury) and mice were then assessed at 10 weeks. In mice treated with FK506 alone, no cell engraftment was observed, whereas addition of FK506 + anti-CD4 antibody mediated engraftment in 50% of animals, where they differentiated mainly into the oligodendrocytic lineage (52.3%), but into the neuronal (<1%) and astrocytic (4.9%) lineages. Locomotor recovery assessment though an open-field test found that mice with engrafted hCNS-SCns had significantly improved recovery with no signs of mechanical allodynia (pain upon contact) of the forepaws or hindpaws, a potential side effect of neural stem cell (NSC) transplantation in animal models of SCI (Hofstetter et al).
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Stem Cell Correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.