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Injected Versus Oral Cyclosporine for Human Neural Progenitor Grafting in Rats

Matthew B. Jensen, Rajeev Krishnaney-Davison, Laura K. Cohen and Su-Chun Zhang

Background: Neural cell transplantation is a promising therapy for stroke, but rejection of human cells in
animal models is an obstacle to furthering this research. Many antirejection strategies have been reported, but few comparison data are available. We asked if human neural cell grafts would have different survival or differentiation with injected or oral cyclosporine regimens.

Methods: Rats received intracerebral grafts of human embryonic stem cell-derived neural progenitors, and 6 rats each were randomized to 4 cyclosporine regimens: 1) daily injections, 2) initial injections followed by oral drug in the drinking water, 3) oral drug only, or 4) no cyclosporine. Histology was performed 14 days after grafting for quantification of markers of human cells, neural cell types, and immune cells.

Results: More rats in the injection (6/6) and injection+oral (5/6) groups had surviving graft cells than in the oral (1/6) and control (3/6) groups (p<0.05), with a trend toward a greater number of surviving graft cells as well. All rats with surviving graft cells also had these cells co-label for a neural progenitor marker, and a minority of graft cells colabeled for a cell division marker and a neuronal marker. Rats with areas of dead graft cell debris were seen in all of the groups. In these areas, cells that labeled for microglial markers also contained the human nuclear marker in their cytoplasm, suggestingphagocytosis of the graft cells.

Conclusions: Human neural cell survival in rat brain tissue differed between cyclosporine regimens, but microglial phagocytosis of graft cells occurred in all the groups. Frequent injection of laboratory animals is undesirable, and a compromise strategy of peritransplant injections followed by drug in the drinking water showed good results in preventing graft cell rejection. Further research is needed to optimize the antirejection approach for this application.