Molecular specification of expanded forebrain neural stem and progenitor cells

Sammanfattning: The molecular specification of neural precursor cells has been suggested to be a progressive process, with a transition from an early requirement for extrinsic signals to intrinsic mechanisms. Thus, the cells in the nervous system acquire distinct fates in response to extrinsic signals, which activate repertoires of transcription factors in a region and cell type specific manner. The studies in this thesis are aimed to increase our understanding as to the extent neural stem and progenitor cells maintain their regional identity during expansion in vitro. To address this issue, cells isolated from different regions of the embryonic or adult mouse and human forebrain were expanded, either as free-floating neurosphere cultures or as attached monolayer cultures. The expression of developmental control genes specific for each region was analyzed in the expanded cells, and their developmental potency was tested both after in vitro differentiation, and after transplantation in vivo. The results show that independent of culture method the expanded cells maintain many aspects of their regional identity. They express developmental control genes characteristic for their area of origin, and upon differentiation they generate neurons characteristic of that area. However, the different culture methods differentially expand specific progenitor populations within each area, and the progenitor composition in the cultures is decisive for the differentiation potential of the expanded cells. Besides its relevance for understanding basic developmental processes, the results may also have an impact on the selection of donor cells and expansion method for cells to be used in cell replacement therapies