Stem Cells And Neuronal Precursors

The advances in our ability to manipulate embryonic stem cells have opened a whole new spectrum of potential therapies in tissue regeneration in general and the brain in particular. It has also reignited interest in brain stem cells and neuroprecursors that show many analogies with the considerably better characterized hematopoietic system. The definition of brain stem cells versus neural precursors is increasingly more precise and tends to better delineate the distinction between totipotent, multipotent, and lineage committed. Excellent reviews about the immense potential of using stem cells in regeneration have been published. The reports that stem cells are present not only in the developing brain but can also be identified in adults have further contributed to the excitement about new possibilities to promote CNS regeneration.

Many of the early studies have often reported successful harvesting of progenitor cells from various regions of the brain (the subventricular zone being the most popular but not singular) that can be expanded in vitro and then differentiate in vivo into functional neurons. The challenge is to still better identify the neural progenitor cells and understand the mechanisms of growth and differentiation from embryonic stem cells. An important characteristic of neuroepi-thelial stem cells, described more than a decade ago and still widely used, is expression of the intermediate filament protein, nestin. More recently, new markers of neuronal progenitor cells, conserved in their evolution and useful for early lineage selection, include Musashi-1 and an epitope recognized by the 2F7 monoclonal antibody. The mechanisms of progenitor cell maturation appear to be similar in various brain regions and seem to depend primarily on a cascade of signals mediated by specific combinations of growth factors and molecules (like noggin) that can modulate their activity.

An understanding of the dynamics of gene expression and specific protein production in the development of the neural lineage from stem cells is critical for designing new isolation and purification methods to be used in vitro for preimplantation neuronal enrichment of future grafts. In addition to the traditional marker nestin, Li and colleagues reported that the transcription factors Sox1 and Sox2 could identify progenitor cells restricted to the neural lineage with higher specificity. Furthermore, expression of a neuron-specific promoter (like Hu and TuJ1/b-III tubulin) offers another opportunity to intervene through gene engineering in the development of neural progenitor cells and select for this cell phenotype.

Regardless of their origin, fetal or adult, neural precursor cells show much promise in brain repair. They can survive and differentiate in the host lesioned brain, although it seems that their predominant differentiation in vivo, posttranplantation is along the astrocytic lineage. Not surprisingly, the migration and differentiation of the grafted precursor cells are significantly influenced by local cues that may even overcome the in vitro manipulations. Nonetheless, the potential for in vivo survival of grafted neural precursor cells can be fully exploited when they are used as platforms for gene delivery or engineered to modulate the neurotrophic factor environment in the host brain.

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