Expanded mesencephalic precursors develop into grafts of densely packed dopaminergic neurons that reinnervate the surrounding striatum and induce functional responses in the striatal neurons

Abstract

The search for alternative sources of dopaminergic cells, other than primary fetal tissue for transplantation in Parkinson's disease has become a major focus of research. Different methodological approaches have led to generation in vitro of cells expressing DA-cell markers, although these cells are frequently unable to survive for a long time in vivo after transplantation and/or induce functional effects in the host brain. In the present study, we grafted cell aggregates treated with antibodies against fibroblast growth factor 4 into dopaminergic-denervated striata in rats. Furthermore, we grafted cell suspensions from primary mesencephalic fetal tissue. Grafts from expanded precursors were able to survive (at least 3 months postgrafting) and most decreased the lesion-induced ipsiversive rotation. In addition, immunolabeling for tyrosine hydroxylase and/or Fos showed that the grafts reinnervated the surrounding striatal tissue with dopaminergic terminals, and induced the expression of Fos in the striatal neurons of the reinnervated area after administration of amphetamine to the host rat. The number of dopaminergic cells in grafts from expanded precursors inducing rotational recovery was usually lower (1,226+/-314) than that in grafts from primary fetal tissue (1,671+/-122), but they were more densely packed in grafts that were of smaller volume and did not have the characteristic central nondopaminergic area observed in grafts from primary fetal tissue. The results suggest that long-term survival and functional integration into the DA-denervated striatum can be achieved with grafts of expanded mesencephalic precursors.