Towards better defined stem cells

R-NSCs have a broad differentiation capacity. These cells refer to a transient stage of NSCs formed from embryonic stem (ES) cells. Delineating the growth requirements and signalling pathways of R-NSCs is central to optimising their exploitation in cell replacement-based therapies. This requires a deeper understanding of cell heterogeneity at the multi-cellular, cellular and molecular level.

To define R-NSC stages and their determinants, the EU-funded MODNEURDEVDIS (Self-renewal, fate potential and plasticity of human embryonic and induced pluripotent stem cell-derived neural stem cells) project used a transgenic ES line that lights up when Notch signalling is activated. This marks stem and progenitor cells in culture and has facilitated the identification of distinct NSC stages in vitro, which represent seminal stages in human neural development. These NSC stages have distinct stem cell properties, cell fate potentials and epigenetic profile. Researchers have observed that the transition from the pluripotent state to the neural lineage is accompanied by widespread DNA methylation changes.

Finally, the consortium has assessed gene expression in long-term cultures of NSCs to discover changes in over 200 transcription factors. Gain or loss of function studies will unveil which genes are responsible for the differentiation of neural progenitors involved in CNS establishment and cortical development.

Apart from fundamental biological insight, the well-defined NSCs will assist in modelling human normal development and delineating the pathogenesis of neurodegenerative diseases. In the long-term, these lines could also be used in drug discovery.