Human Pluripotent Stem Cell-Derived Cerebellar Neurons: From Development to Modeling Cerebellar Ataxias

Abstract

The most affected cell types in cerebellar ataxias are the cerebellar neurons, which are not readily accessible for cellular and molecular investigation. Pluripotent stem cell (PSC) technology has emerged as an important tool for generating diverse types of neurons, which are used in order to better understand the human nervous system development and pathologies. In this chapter, the strategies for the differentiation of human PSCs toward cerebellar neurons are overviewed, followed by an outlook of their further optimization and diversification by implementing the knowledge from cerebellar development and new cell culture approaches. The optimization stategies are based on the recent progress made in defining the cell populations in mature and developing mouse and human cerebellum. The cellular phenotypes and organization in mouse and human cerebellum are briefly presented, followed by an overview of our current knowledge about their development, which includes pattering, proliferation, neurogenesis, gliogenesis, migration, connectivity and maturation. To date, however, relatively few studies have used induced PSCs (iPSCs) to model cerebellar ataxias and even fewer have looked directly to cerebellar neurons. The reported iPSC-derived in vitro models for cerebellar ataxias are reviewed, followed by an outlook of how to improve these models by generating and exporing the cerebellar neurons.