of pluripotent cells from grafts. Neuroepithelial tumors have been found in grafts of hESC-derived neural stem cells and their derived neuronal progenitors (Roy et al., 2006), as well as in grafts of cultured NSCs expanded for prolonged periods under constant mitogenic stimulation (Amariglio et al., 2009). Nonetheless, few studies have sought to specifically rule out the presence of neural or glial tumors in hESC or hiPSC-derived graft recipients. Long-term survival studies over broad dose ranges, with rigorous and unbiased neuropathological analysis, will need to be done in experimental animals to ensure the lack of tumorigenicity of hESC and hiPSC derivatives. Importantly, these safety studies will need to be partnered with efficacy studies utilizing the same protocols, recognizing that the long in vitro differentiation protocols that may mitigate the risk of tumorigenesis do not come without a price; prolonged differentiation may limit the expansion and dispersal capability, and ultimately the utility, of the engrafted donor cells.
