In vitro human stem cell-mediated central nervous system platforms: Progress and challenges

The need for human cell-based experimental platforms for the study of the brain’s most basic activity and function has never been greater. Initial progress was made through differentiation of the NT2.D1 platform, which facilitated the study of postmitotic but generic neuronal/astrocytic interactions both electrophysiologically and pharmacologically. However, induced pluripotent stem cell (iPSC) platforms can form specific neuronal and astrocytic subpopulations which are identical to those of a functioning area of the brain. Hence, not only functionality can be modeled with iPSC-derived platforms but also specific dysfunctionality in these areas, such as is seen in neurodegenerative disease. Crucially, it has become clear that the contents of the extracellular matrix (ECM) of the living brain have a disproportionate influence not only on cell development and maturity but also continued maintenance of function. For iPSC models to ascend to this level of authenticity requires new methods and technology to include a fully functional ECM in more complete models of specific brain areas. Future approaches in ECM formation, alongside more rapid iPSC-derived tissue formation through lineage reprogramming, will eventually bring human experimental platforms to a more advanced stage of development, which will be combined with the necessary flexibility and practicality for diverse applications ranging from basic research through to drug discovery.