Fate mapping and lineage analyses demonstrate the production of a large number of striatal neuroblasts after transforming growth factor alpha and noggin striatal infusions into the dopamine-depleted striatum

Stem Cells. 2008 Sep;26(9):2349-60. doi: 10.1634/stemcells.2008-0080. Epub 2008 Jun 12.

Abstract

Infusion of transforming growth factor alpha (TGFalpha) 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 TGFalpha 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 TGFalpha 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 TGFalpha 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 TGFalpha-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 TGFalpha 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Carrier Proteins / pharmacology*
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Corpus Striatum / cytology*
  • Corpus Striatum / metabolism
  • Dopamine / deficiency*
  • Female
  • Intermediate Filament Proteins / metabolism
  • Mice
  • Neostriatum / cytology
  • Neostriatum / metabolism
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neuroepithelial Cells / cytology
  • Neuroepithelial Cells / metabolism
  • Neurons / cytology*
  • Neurons / metabolism
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / pharmacology
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Transforming Growth Factor alpha / pharmacology*

Substances

  • Carrier Proteins
  • Intermediate Filament Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nes protein, rat
  • Nestin
  • Proliferating Cell Nuclear Antigen
  • Recombinant Proteins
  • Transforming Growth Factor alpha
  • noggin protein
  • Dopamine