The potential for circuit reconstruction by expanded neural precursor cells explored through porcine xenografts in a rat model of Parkinson's disease

Neural precursors with the properties of neural stem cells can be isolated from the developing brain, can be expanded in culture, and have been suggested as a potential source of cells for neuronal replacement therapies in degenerative disorders such as Parkinson's disease (PD). Under such conditions an improved spectrum of functional benefit may be obtained through homotypic reconstruction of degenerated neural circuitry, and to this end we have investigated the potential of expanded neural precursor cells (ENPs) to form long axonal projections following transplantation in the 6-hydroxydopamine-lesioned rat model of PD. ENPs have been isolated from the embryonic pig, since implantation in a xenograft environment is thought to favor axonal growth. These porcine ENPs possessed similar properties in vitro to those described in other species: they proliferated in response to epidermal and fibroblast growth factor-2, expressed the neuroepithelial marker nestin, and differentiated into neurons, astrocytes, and occasional oligodendrocytes on mitogen withdrawal. The use of pig-specific markers following xenotransplantion into cyclosporin A-immunosuppressed rats revealed that many cells differentiated into neurons and displayed extensive axogenesis, such that when placed in the region of the substantia nigra fibers projected throughout the striatal neuropil. These neurons were not restricted in the targets to which they could project since following intrastriatal grafting fibers were seen in the normal striatal targets of the pallidum and substantia nigra. Staining for a pig-specific synaptic marker suggested that synapses were formed in these distant sites. A small number of these cells differentiated spontaneously to express a catecholaminergic phenotype, but were insufficient to mediate behavioral recovery. Our results suggest that when the efficiency of neurochemical phenotype induction is increased, ENP-derived neurons have the potential to be a uniquely flexible source of cells for therapeutic cell replacement where anatomical reconstruction is advantageous. (C) 2002 Elsevier Science (USA).