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TISSUE-SPECIFIC STEM CELLS

Fate Mapping and Lineage Analyses Demonstrate the Production of a Large Number of Striatal Neuroblasts After Transforming Growth Factor and Noggin Striatal Infusions into the Dopamine-Depleted Striatum

^aUdall Parkinson Disease Research Center of Excellence, Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA;
^bDepartment of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Key Words. Parkinson's disease • Adult neurogenesis • Subventricular zone • Striatum • Transforming growth factor • Neuroblasts

Correspondence: Correspondence: Ole Isacson, M.D., Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, MRC I, 115 Mill Street, Belmont, Massachusetts 02478, USA. Telephone: 617-855-3283; Fax: 617-855-2522; e-mail: isacson{at}hms.harvard.edu

Received on February 8, 2008; accepted for publication on June 4, 2008.

First published online in STEM CELLS EXPRESS  June 12, 2008.

Infusion of transforming growth factor (TGF) into the adult dopamine (DA)-depleted striatum generates a local population of nestin⁺/proliferating cell nuclear antigen (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. Experiments in rats using 5-bromo-2'-deoxyuridine (BrdU) to label neural progenitor cells showed that during TGF infusion in the DA-depleted striatum, newborn striatal cells formed a homogeneous population of precursors, with the majority coexpressing nestin, Mash1, Olig2, and epidermal growth factor receptor, consistent with the phenotype of multipotent C cells. Upon TGF pump withdrawal, the subventricular zone (SVZ) was repopulated by neuroblasts. Strikingly, during this period, numerous clusters of doublecortin⁺/polysialylated neuronal cell adhesion molecule⁺ neuroblasts were also produced in the ipsilateral medial striatum. In parallel, striatal BrdU⁺/glial fibrillary acidic protein⁺ astrocytes were generated, but no BrdU⁺/O4⁺/CNPase⁺ oligodendrocytes were generated. Infusion of the neuralizing bone morphogenetic protein antagonist noggin after TGF 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 treatment condition were differentiated neurons generated, including DA neurons. Using 6-hydroxydopamine-lesioned nestin-CreER^T2/R26R-YFP mice that allow genetic fate-mapping of SVZ nestin⁺ cells, we show that TGF-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 TGF 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.

Disclosure of potential conflicts of interest is found at the end of this article.

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