Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells

Cell therapy raises high hopes for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from two distant embryonic SCs lines (H9 and RC17) to express one of four prosurvival factors - Hif1a, Akt1, Bcl-2, or Bcl-xl - and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, three out of four modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation towards neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.