Human neural precursor cells express low levels of telomerase in vitro andshow diminishing cell proliferation with extensive axonal outgrowth following transplantation

Worldwide attention. is presently focused on proliferating populations of n eural precursor cells as an in vitro source of tissue for neural transplant ation and brain repair. However, successful neuroreconstruction is continge nt upon their capacity to integrate within the host CNS and the absence of tumorigenesis, Here we show that human neural precursor cells express very low levels of telomerase at early passages (less than 20 population doublin gs), but that this decreases to undetectable levels at later passages. In c ontrast, rodent neural precursors express high levels of telomerase at both early and late passages. The human neural precursors also have telomeres ( approximately 12 kbp) significantly shorter than those of their rodent coun terparts (approximately 40 kbp), Human neural precursors were then expanded 100-fold prior to intrastriatal transplantation in a rodent model of Parki nson's disease. To establish the effects of implanted cell number on surviv al and integration, precursors were transplanted at either 200,000, 1 milli on, or 2 million cells per animal. Interestingly, the smaller transplants w ere more likely to extend neuronal fibers and less likely to provoke immune rejection than the largest transplants in this xenograft model. Cellular p roliferation continued immediately posttransplantation, but by 20 weeks the re were virtually no dividing cells within any of the grafts. In contrast, fiber outgrowth increased gradually over time and often occupied the entire striatum at 20 weeks postgrafting, Transient expression of tyrosine hydrox ylase-positive cells within the grafts was found in some animals, hut this was not sustained at 20 weeks and had no functional effects, For Parkinson' s disease, the principal aim now is to induce the dopaminergic phenotype in these cells prior to transplantation. However, given the relative safety p rofile for these human cells and their capacity to extend fibers into the a dult rodent brain, they may provide the ideal basis for the repair of other lesions of the CNS where extensive axonal outgrowth is required. (C) 2000 Academic Press.