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. 2018 Sep 26;12:646.
doi: 10.3389/fnins.2018.00646. eCollection 2018.

The Use of Stem Cell-Derived Neurons for Understanding Development and Disease of the Cerebellum

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Free PMC article

The Use of Stem Cell-Derived Neurons for Understanding Development and Disease of the Cerebellum

Samuel P Nayler et al. Front Neurosci. .
Free PMC article

Abstract

The cerebellum is a fascinating brain structure, containing more neurons than the rest of the brain combined. The cerebellum develops according to a highly orchestrated program into a well-organized laminar structure. Much has been learned about the underlying genetic networks controlling cerebellar development through the study of various animal models. Cerebellar development in humans however, is significantly protracted and more complex. Given that the cerebellum regulates a number of motor and non-motor functions and is affected in a wide variety of neurodevelopmental and neurodegenerative disorders, a better understanding of human cerebellar development is highly desirable. Pluripotent stem cells offer an exciting new tool to unravel human cerebellar development and disease by providing a dynamic and malleable platform, which is amenable to genetic manipulation and temporally unrestricted sampling. It remains to be seen, however, whether in vitro neuronal cultures derived from pluripotent stem cells fully recapitulate the formation and organization of the developing nervous system, with many reports detailing the functionally immature nature of these cultures. Nevertheless, recent advances in differentiation protocols, cell-sampling methodologies, and access to informatics resources mean that the field is poised for remarkable discoveries. In this review, we provide a general overview of the field of neuronal differentiation, focusing on the cerebellum and highlighting conceptual advances in understanding neuronal maturity, including a discussion of both current and emerging methods to classify, and influence neuroanatomical identity and maturation status.

Keywords: Purkinje cell; ataxia; cerebellum; differentiation; granule cell; neuronal; organoid; stem cell.

Figures

FIGURE 1
FIGURE 1
Saggital depiction of human hindbrain at post-conception week 15. EGLU, external granule layer; CBC, cerebellar cortex; HWM, white matter of hindbrain; CBDN, cerebellar deep nuclei; 4V, fourth ventricle; VZCB, ventricular matrix zone of cerebellum; VZMO, ventricular matrix zone of medulla; URL, upper rhombic lip; LRL, lower rhombic lip; Cho4V, choroid plexus of the fourth ventricle; PnbB, pontobulbar body; CEMS, caudal (posterior) extramural migratory stream; Mo, medulla oblongata; 8ve, vestibular nuclei in medulla; 10N [(dorsal motor nucleus of the vagus, vagal nucleus)], Sol, solitary nucleus; sol, solitary tract; Ecu, external cuneate nucleus; Sp5, spinal trigeminal matrix. Image taken with permission from the Allen Brain Atlas (http://atlas.brain-map.org) [Accessed 2018].
FIGURE 2
FIGURE 2
Summary of key approaches being utilized synergistically with organoid technology. A cerebellar organoid is shown in the center. Approaches clockwise from top: Rapid developments in single-cell sequencing technologies drive new methods of population profiling. Shown is a tSNE plot constructed from the 10X Million Cell Dataset (data accessible at NCBI GEO database, accession GSM2453144). Pathway analysis is a broad set of approaches commonly utilizing differential expression and gene-set enrichment analysis methods to identify coordinately dysregulated genes as representative of specific pathway perturbations. Transplantation offers a means to test cellular plasticity, lineage commitment, and factors required for terminal differentiation (figure depicting P14 mouse cerebellum has been adapted from the Allen Brain Atlas). Niche bioengineering allows the in vitro reconstruction of elements of the in vivo niche, using approaches such as 3D printing, hydrogels, microfabricated devices, and co-culture. Drug screening stands to benefit from organoids by providing physiologically relevant surrogate model systems for the organ of interest for high-throughput testing. Electrophysiology is a widely adopted tool for establishing neuronal maturity and connectivity (trace adapted from Nayler et al., 2017).

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    van Essen MJ, Nayler S, Becker EBE, Jacob J. van Essen MJ, et al. PLoS Genet. 2020 Apr 16;16(4):e1008630. doi: 10.1371/journal.pgen.1008630. eCollection 2020 Apr. PLoS Genet. 2020. PMID: 32298260 Free PMC article. Review.

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