MODNEURDEVDIS

"Title: Self-Renewal, Fate Potential and Plasticity of Human Embryonic and Induced Pluripotent Stem Cell-Derived Neural Stem cells"

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 Obiettivo del progetto (Objective)

'Neural stem cells (NSCs) can propagate in vitro while retaining ability to differentiate into neurons, astrocytes and oligodendrocytes. However, because of the nature of their developmental progression, NSCs isolated at different developmental stages or regions exhibit remarkable differences in their ability to yield specific neuron types. Specifically, NSCs grown in vitro rapidly lose access to the full neuronal spectrum. Limited NSC potential is one of the major impediments for applications in regenerative medicine, specifically for Parkinson’s and motoneuron-related diseases. Therefore, there is an enormous need to understand how NSCs self-renew. Human embryonic stem cells (hESCs) are known to provide access to early neural fates. We have recently isolated a novel type of early NSCs derived from hESCs termed rosette-NSCs (R-NSCs), which respond to such regional patterning cues. We proved the unique NSC stage of R-NSCs based on their cytoarchitecture, marker expression, stem cell properties and differentiation potential. Nevertheless, we only partially identified growth requirements and signaling pathways governing the R-NSCs stage. Here we would like to address these limitations by defining heterogeneity within R-NSCs and develop genetic strategies to prospectively isolate fully patternable R-NSCs. Generating transgenic hESC reporter lines will serve as reliable readout for defining R-NSC stage, identity and function, and will be used for establishing correlative genome-wide chromatin state and promoter methylation maps. Finally we will systematically probe function of extrinsic/intrinsic factors affecting R-NSC identity, neural patterning potential and epigenetic state. This should provide fundamental insights into the genetic/epigenetic mechanisms of neural patterning and ultimately result in novel conditions for the continued in vitro expansion of fully patternable R-NSC - a key step towards establishing a stable expandable universal NSC population.'

Introduzione (Teaser)

European scientists are working to characterise neural stem cells (NSCs) for cell therapy applications.

Descrizione progetto (Article)

NSCs possess an inherent capacity to differentiate into different cell types. However the ability of cultured NSCs to produce clinically-relevant neuronal types is gradually lost. To produce clinically-relevant neuronal types, rosette-NSCs (R-NSCs) show promise.

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.