Central Nervous System Organoids

Limitations of Using Animal Models for CNS Research 

Animal models have traditionally been used to study the central nervous system (CNS) and neurodegenerative disorders. However, critical differences in the anatomy and physiology of rodent and human brains significantly influence the quality of information obtained from such studies. Non-human primate brains are more closely related to the human brain in structure and function. Nevertheless, the cost and ethical concerns restrict their use in research.

Introduction to Brain Organoids

Brain organoids present a possible solution to the challenges of using animal models in the study of neurological diseases. Unlike animal models, brain organoids model various cell types in different regions of the brain and closely recapitulate critical features of the human brain in-vivo. Advances in organoids and the use of induced pluripotent stem cells allow for the development of region-specific organoids. Disease-specific organoids are made using patient-derived induced pluripotent cells. These brain organoids could contribute to the study of neuronal development and related conditions such as autism spectrum disorders, microcephaly, and macrocephaly. One exciting application of brain organoids is the study of altered signaling pathways in neuropsychiatric diseases.

Challenges Using CNS Organoids in Research

CNS organoids can undergo apoptosis and necrosis of the core during the long-term culturing which is required to study Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. One way to increase the duration of viable cultures is to introduce vasculature in the grafting organoids. A second solution is to expose the slices to an air-liquid interface for efficient gas and nutrient exchange. Co-culturing CNS organoids with Human Vascular Endothelial Cells (HUVECs) creates vascular organoids which allow long-term studies up to 200 days without developing necrotic core.
 

Figure 1: Comparison of normal and diseased brain in patient with Alzheimer's disease. 


Various Methods of Generating CNS Organoids

There are two different methods to generate CNS organoids. These methods are called unguided and guided. The unguided process involves pluripotent stem cells which organize into defined structures without any outside help. However, the drawback of this technique is variations in cell populations, cell lineages, and organoid size.

The guided method involves exposing the cells to specific factors that control the organoid formation. These particular factors create organoids of distinct lines by triggering signaling pathways. These factors could generate consistent proportions of mixed cell types. For instance, Smad inhibitors direct the organoids to ectoderm lineage and away from endoderm and mesoderm lineage. The organoids' developments make them better suited for culturing studies over more extended periods. Long-term disease-specific organoids could contribute to studies of neurodegenerative conditions and testing the efficacy of drug candidates.

Brain Organoids: Promising Models

Brain organoids are a promising model for the future of neurological research and drug development. They provide an ethical solution to bridge the species gap in the neurological study and work efficiently for long term studies and could open the doors to new treatments to help treat neurodegeneration and related conditions.

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