Human Neural Stem Cells for Human Brain Repair – Challenges and Strategies

The generation of specific neuronal and glial cell types for brain repair and drug discovery are of major interest to the stem cell and biomedical community. Pluripotent stem cells (PSCs) serve as an unlimited, substantially homogeneous cell source for mimicking the production of such cell types due to their ability to self-replicate indefinitely in vitro while retaining potential for multi-lineage differentiation. Neural stem cells (NSCs) are building blocks of brain development that can be isolated from the CNS but can also be derived from PSCs. Similar to PSCs, also NSCs are known to hold high proliferative capacity while retaining multipotency – that is the potential to differentiate to the three neural lineages – neurons, astrocytes and oligodendrocytes.

However, unlike PSCs, the differentiation potential of cultured NSCs towards specifically desired and clinically relevant cell types is very limited.

How is that so? NSC cultures are enormously heterogeneous. The heterogeneity of NSCs is irrespective of their origin or age, whether isolated from a certain brain region or a certain developmental stage, or derived from PSCs. While in vivo, NSCs are programmed to create cell diversity, in the absence of the exact instructive signals in vitro NSCs are destined to yield diversifying progeny as they progress in culture. This is also the reason why - in contrast to PSCs - definitive NSC lines that combine high proliferative capacity, consistent cell homogeneity and perpetuating developmental potency during extended culture hardly exist. In fact, there is no formula - a cocktail set of culture conditions - that can maintain the full identity of distinct NSC types as homogeneous, self-renewing populations.

One of the major long-term goals of our lab is to develop strategies for generating unlimited sources of homogeneous NSC types. In analogy to PSCs that serve as indefinite cell sources for all tissues, unlimited sources of distinct types of homogeneous, self-replicating NSCs – with each type retaining its own unique potential through extensive culture – will create a paradigm shift in how we percept NSC biology.

Such populations will serve as prototypic universal cellular platforms that will accelerate the understanding of how distinct neural fates develop, will streamline the making of pure neuronal and glial populations, will foster amenability towards modelling specific brain functions in health and degeneration, will standardize pharmacological or genetic screens towards discovering novel drugs, and will set the stage for making pure cells for future cell replacement-based therapy.

We are very fascinated by this fundamental question in stem cell biology: Where and when is heterogeneity of cultured NSCs initiated? in what ways does it contribute to brain cell type diversity? how can we develop strategies to gain knowledge on these processes and later use it for harnessing the full potential of NSCs for regenerative medicine?

Tackling this roadblock necessitates deep understanding of how cell fate decisions that occur in NSCs during development in vivo are ultimately translated into the progressive heterogeneity we observe in NSCs during culture in vitro. Addressing this question should eventually lead to taking the full advantage of using NSCs towards the establishment of precise conditions that control dynamics of NSC potential in culture, and ultimately towards generating various neuronal and glial cell types that are clinically relevant for so many neurological diseases.

In our lab, we aim at developing experimental paradigms at various disciplines to systematically distinguish apart distinct types of progenitors that coexist in the culture dish. This allows us to identify, isolate and characterize new types of neural stem and progenitor cells, and ultimately use all this information to establish innovative culture techniques for generating unlimited neural stem cell sources for deriving essentially any desired type of a neuronal or glial cell type.

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