Critical involvement of Rho GTPase activity in the efficient transplantation of neural stem cells into the injured spinal cord

Background: Transplantation of neural stem/progenitor cells is a promising approach toward functional restoration of the damaged neural tissue, but the injured spinal cord has been shown to be an adverse environment for the survival, migration, and differentiation of the donor cells. To improve the efficiency of cell replacement therapy, cell autonomous factors in the donor cells should be optimized. In light of recent findings that Rho family GTPases regulate stem cell functions, genetic manipulation of Rho GTPases can potentially control phenotypes of transplanted cells. Therefore we expressed mutant forms of Rho GTPases, Rac, Rho, and Cdc42, in the neural stem/progenitor cells and examined their survival and migration after transplantation. Results: Manipulation of the individual Rho GTPases showed differential effects on survival, with little variation in their migratory route and predominant differentiation into the oligodendroglial lineage. Combined suppression of both Rac and Rho activity had a prominent effect on promoting survival, consistent with its highly protective effect on drug-induced apoptosis in culture. Conclusion: Manipulation of Rac and Rho activities fully rescued suppression of cell survival induced by the spinal cord injury. Our results indicate that precise regulation of cell autonomous factors within the donor cells can ameliorate the detrimental environment created by the injury.