CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening

Abstract

The paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.

Figure 1.

Schematic of cerebral organoid development. Organoids developed from the embryoid bodies using induced pluripotent stem cell (iPSC)-derived cells that were grown in neural induction medium to generate neuroectoderm that were embedded in Matrigel® and allowed to grow in a spinning bioreactor or orbital shaker for better diffusion to obtain the 3D cerebral organoids. On exposure to retinoic acid, cerebral organoids self-organize through self-patterning mechanisms to display diverse populations of neural progenitors including radial glia, which expand forming cerebral structures [24].

Figure 2.

Approaches for developing organoids. (a) Unguided approach. Organoids can be developed by relying on the self-organizing properties of the stem-cell aggregates producing cerebral or whole organoids. The resulting cerebral organoids often contain heterogeneous tissues resembling various brain regions. (b) Guided approach. Organoids can be differentiated into brain-region-specific organoids by guided differentiation in the presence of external patterning factors. Two or more guided brain organoids can also be fused together to model the interaction between different brain regions.

Figure 3.

Compilation of different methods used for developing different brain regions in central nervous system (CNS) organoids. The illustration represents the different modeling methods established to produce region specific CNS organoids. Reproduced, with permission, from [89].

Figure 4.

Modern applications of cerebral organoids. (a) Interspecies evolution. Organoids have provided much opportunity to study human brain evolution in comparison with other species such as apes, where very limited brain models are available. (b) Congenital brain deformation. They have also provided a unique opportunity to model disorders with cerebral malformations such as microcephaly caused by infectious diseases or genetic alterations. (c) Neurodegenerative disease. The current organoid model only recapitulates fetal brain, various groups have also used them to model neurodegenerative disorders like Alzheimer’s disease and schizophrenia. (d) Gene editing. Researchers have developed organoids from reprogrammed induced pluripotent stem cells (iPSCs) using genome-editing techniques such as CRISPR/Cas9 to model neurodegenerative disorders, disorders with genetic defect or to study brain tumors by inducing mutations. (e) Drug compound screening. Organoids have also been used for high-throughput drug screening to carry out drug efficacy and toxicity studies to evaluate drug exposure defects on fetal brain. (f) Disease pathology. Organoids have also been used to study infectious diseases such as Zika virus and its associated fetal brain defects.