For decades, most of our understanding of brain development and diseases affecting the central nervous system (CNS) has been based on traditional two-dimensional cell cultures and animal models. While many experimental methods rely on rodents or non-human primates, the brains of these animals differ substantially from those of humans in terms of both their structure and function. For example, the human brain contains a human-exclusive outward-expanded subventricular zone (oSVZ) that increases the volume and function of the mature cerebrum. Anthropological studies have revealed that the human brain contains more elaborate cytoarchitectonic subdivisions than the brains of lissencephalic primates and gyrencephalic rodents. Besides, animal brains exhibit a lower encephalization quotient, lower neuronal density, and distinct permutation characteristic when compared with those of humans. Therefore, preclinical experiments using conventional models sometimes lead to disappointing results in disease modeling and drug screening studies.
Three-dimensional cerebral organoids form more heterogeneous structures in vitro, eventually developing into different progenitor zones and taking on the characteristics of various brain regions. Since these systems more closely mirror the spatial architecture of the brain in vivo, they can be used to study pathophysiological processes as well as the effects of genetic manipulation on such processes.
Fig.1 Schematic diagram representing cerebral organoid generation from human induced pluripotent stem cells (hiPSCs). (Liu, 2019)
Applications of Whole-brain Organoid in Research
Neuropsychiatric diseases such as schizophrenia, depression, and autism spectrum disorder (ASD) have complex disease profiles, affecting multiple aspects of cognition, personality, and perception. Due to such complexities in symptomatology, polygenetic etiology, and the limited availability of diagnostic markers/research models, neuropsychiatric diseases, which are now considered neurodevelopmental in origin, have been difficult to study experimentally and remain poorly understood.
Fig.2 Schematic drawing of brain organoid generation and translational applications. (Liu, 2019)
Schizophrenia and ASD
Cerebral organoids have become a new avenue for modeling developmental abnormalities and genetic alterations associated with neuropsychiatric disease. Indeed, such models have been used to uncover the cellular phenotypes and pathophysiological mechanisms underlying disorders such as schizophrenia and ASD. Yoon et al. used hiPSC-derived cortical neural rosettes to study the molecular mechanisms underlying schizophrenia, observing that 15q11.2 haploinsufficiency leads to NSC deficits associated with adherens junctions. The authors further noted that CYFIP1 and WAVE signaling plays an important role in generating schizophrenia phenotypes.
Miller-Dieker syndrome (MDS)
Miller-Dieker syndrome (MDS) is another severe neurodevelopmental disease with dramatic cortical malformation. Reduced neuroepithelial loops have been developed in cerebral organoids generated from MDS patients, with smaller sizes compared with control organoids. Studies using telencephalic organoids derived from hiPS cells of MDS patients found evidence of prolonged mitosis of outer radial glia cells, increased apoptosis of neuroepithelial stem cells, and increased vertical spindle orientation. Researchers using cerebral organoids to explore the mechanism of Sandhoff disease found accumulated GM2 ganglioside and impaired neuronal differentiation altered by the disease process.
These studies demonstrated that cerebral organoids can be broadly used to unravel the pathogenic cellular mechanisms of neurodevelopmental diseases.
Cerebral organoids can be used to model neurodevelopmental and infectious diseases.
Cerebral organoids are superior to traditional neuroepithelium methods.
Cerebral organoid methods require more specialized and complex culture conditions.
Cerebral organoid is a powerful tool in CNS diseases research.
Services at Creative Biolabs
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Liu, F., et al. Advances in Cerebral Organoid Systems and their Application in Disease Modeling. Neuroscience. 2019, 399: 28-38.