Transplanted human neural precursor cells migrate widely but show no lesion-specific tropism in the 6-hydroxydopamine rat model of Parkinson's disease.

Parkinson's disease (PD), while primarily associated with degeneration of nigrostriatal dopamine neurons, is now increasingly recognized to have more widespread cell loss and so the most effective cell replacement therapy should target all these neuronal losses. Neural precursor cells might be ideal in this regard as in certain circumstances they have been shown to migrate widely following transplantation into the CNS. The aim of this study was to investigate whether transplanted human expanded neural precursor cells (hENPs) could migrate to sites of established or evolving pathology in the adult brain using the 6-hydroxydopamine (6-OHDA) rat model of PD. hENPs were grafted into the striatum prior to, at the same time as, or after the animals received a 6-OHDA lesion to the medial forebrain bundle. The presence of donor cells was then assessed in a distant site of cell loss (substantia nigra) or sites where cell death would not be expected (frontal cortex and globus pallidus). Donor cells were found distant from the site of implantation but the migration of these hENPs was not significantly greater in the 6-OHDA-lesioned brain and the cells did not specifically target the site of cell loss in the substantia nigra. The temporal relationship of grafting relative to the lesion, and therefore dopaminergic cell death, did not affect the migration of hENPs nor their differentiation. We conclude that while transplanted hENPs are capable of migration away from the site of implantation, they show no specific tropism for sites of ongoing or established nigral dopaminergic cell loss in this lesion model. Therefore, the use of such cells to replace the range of neurons lost in PD is likely to require a deeper understanding of the migratory cues in the damaged adult brain and some manipulation of these cells prior to transplantation.

Staging and preparation of human fetal striatal tissue for neural transplantation in Huntington's disease.

Transplantation of human fetal central nervous system tissue has been shown to be of benefit in Parkinson's disease, and is currently being explored as a therapeutic option in Huntington's disease. The success of a neural transplant is dependent on a number of factors, including the requirement that donor cells are harvested within a given developmental window and that the cell preparation protocols take account of the biological parameters identified in animal models. Although many of the criteria necessary for a successful neural transplant have been defined in animal models, ultimately they must be validated in human studies, and some issues can only ever be addressed in human studies. Furthermore, because neural transplantation of human fetal tissue is limited to small numbers of patients in any one surgical center, largely due to practical constraints, it is crucial that tissue preparation protocols are clearly defined and reproducible, so that (i) multicenter trials are possible and are based on consistent tissue preparation parameters, and (ii) results between centers can be meaningfully analyzed. Here we describe the preparation of human fetal striatum for neural transplantation in Huntington's disease, and report on the validation of a method for estimating the developmental stage of the fetus based on direct morphometric measurements of the embryonic tissue.