Infusion of TGFα into the adult dopamine (DA)-depleted striatum generates a local population of nestin+/PCNA+ newborn cells . The precise origin and fate of these new striatal cells are unknown, making it difficult to direct them for neural repair in Parkinson’s disease (PD). Experiments in rats using BrdU to label neural progenitor cells (NPCs) showed that during TGFα infusion in the DA-depleted striatum, newborn striatal cells formed a homogenous population of precursors, with the majority coexpressing nestin, Mash1, Olig2 and EGFR, consistent with the phenotype of multipotent C cells. Upon TGFα pump withdrawal, the subventricular zone (SVZ) was repopulated by neuroblasts. Strikingly, during this period, numerous clusters of DCX+/PSANCAM+ neuroblasts were also produced in the ipsilateral medial striatum. In parallel, striatal BrdU+/GFAP+ astrocytes were generated, but no BrdU+/O4+/CNPase+ oligodendrocytes. Infusion of the neuralizing BMP antagonist noggin after TGFα pump withdrawal increased the neuroblast to astrocyte ratio among new striatal cells by blocking glial differentiation, but did not alter striatal neurogenesis. At no time or no treatment condition were differentiated neurons generated, including DA neurons. Using 6-OHDA lesioned nestin-CreERT2/R26R-YFP mice that allow genetic fate-mapping of SVZ nestin+ cells, we show that TGFα-generated striatal cells originate from SVZ nestin+ precursors that confirmed data from the rats on the phenotype and fate of striatal nestin+/PCNA+ cells upon TGFα withdrawal. This work demonstrates that a large population of multipotent striatal C-like cells can be generated in the DA-depleted striatum that do not spontaneously differentiate into DA neurons.
Keywords: Parkinson’s disease, adult neurogenesis, subventricular zone, striatum, TGFα, neuroblasts