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Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution.
Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Despite metabolic differences, organoid models preserve gene regulatory networks related to primary cell types and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoids and macaque cortex, enriched for recent gene duplications, and including multiple regulators of PI3K-AKT-mTOR signaling. We observed increased activation of this pathway in human radial glia, dependent on two receptors upregulated specifically in human: INSR and ITGB8. Our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.
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Brain organoids: A new tool for modelling of neurodevelopmental disorders.
Neurodevelopmental disorders are mostly studied using mice as models. However, the mouse brain lacks similar cell types and structures as those of the human brain. In recent years, emergence of three-dimensional brain organoids derived from human embryonic stem cells or induced pluripotent stem cells allows for controlled monitoring and evaluation of early neurodevelopmental processes and has opened a window for studying various aspects of human brain development. However, such organoids lack original anatomical structure of the brain during maturation, and neurodevelopmental maturation processes that rely on unique cellular interactions and neural network connections are limited. Consequently, organoids are difficult to be used extensively and effectively while modelling later stages of human brain development and disease progression. To address this problem, several methods and technologies have emerged that aim to enhance the sophisticated regulation of brain organoids developmental processes through bioengineering approaches, which may alleviate some of the current limitations. This review discusses recent advances and application areas of human brain organoid culture methods, aiming to generalize optimization strategies for organoid systems, improve the ability to mimic human brain development, and enhance the application value of organoids.
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Brain Organoids in Neurodegenerative Disease Modeling: Advances, Applications and Future Perspectives.
Neurodegenerative diseases (NDDs) represent incurable and debilitating conditions characterized by progressive deterioration of neurological function. Investigating neurodegeneration remains a critical global challenge in aging societies. Brain organoids-self-organizing three-dimensional structures derived from human pluripotent stem cells-recapitulate cell types and cytoarchitectures of the developing human brain. This in vitro model system has advanced our bridge between conventional two-dimensional cultures and in vivo models. Brain organoids emulate early neural tube formation, neuroepithelial differentiation, and whole-brain regionalization. Furthermore, region-specific organoid models now facilitate mechanistic investigation into acquired and inherited NDDs' pathogenesis, alongside drug discovery and toxicity screening. In this review, we (i) delineate the epidemiology and pathobiology of major NDDs, (ii) analyze limitations of current animal models, (iii) critically evaluate brain organoid generation methodologies, and (iv) focus on organoid applications in modeling Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).
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Applications of Brain Organoids for Infectious Diseases.
Brain organoids are self-organized three-dimensional aggregates generated from pluripotent stem cells. They exhibit complex cell diversities and organized architectures that resemble human brain development ranging from neural tube formation, neuroepithelium differentiation, neurogenesis and gliogenesis, to neural circuit formation. Rapid advancements in brain organoid culture technologies have allowed researchers to generate more accurate models of human brain development and neurological diseases. These models also allow for direct investigation of pathological processes associated with infectious diseases affecting the nervous system. In this review, we first briefly summarize recent advancements in brain organoid methodologies and neurodevelopmental processes that can be effectively modeled by brain organoids. We then focus on applications of brain organoids to investigate the pathogenesis of neurotropic viral infection. Finally, we discuss limitations of the current brain organoid methodologies as well as applications of other organ specific organoids in the infectious disease research.
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Deriving early single-rosette brain organoids from human pluripotent stem cells.
Brain organoid methods are complicated by multiple rosette structures and morphological variability. We have developed a human brain organoid technique that generates self-organizing, single-rosette cortical organoids (SOSR-COs) with reproducible size and structure at early timepoints. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D developmental transition from neural plate to neural tube. Most monolayer fragments form spheres with a single central lumen. Over time, the SOSR-COs develop appropriate progenitor and cortical laminar cell types as shown by immunocytochemistry and single-cell RNA sequencing. At early time points, this method demonstrates robust structural phenotypes after chemical teratogen exposure or when modeling a genetic neurodevelopmental disorder, and should prove useful for studies of human brain development and disease modeling.
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Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models.
AIMS: To investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets. METHODS: We systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models. RESULTS: Behavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level. CONCLUSIONS: Semaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.
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Human Brain Organoids: Development and Applications.
Brain organoids are three-dimensional structures generated from pluripotent stem cells, closely resembling the embryonic human brain. They exhibit gene expression patterns and signaling pathways similar to those in the developing human brain, facilitating the study of the molecular mechanisms underlying brain development, as well as genetic and environmental factors underlying developmental disorders. A brain organoid comprises various cell types noted in a developing brain: neurons, astrocytes, microglia, and oligodendrocytes. These cells interact with each other and form complex networks, enabling the investigation of communication among different cell types and their contribution to brain function. Brain organoid structure is also similar to that of a developing human brain, with distinct features resembling regions such as the cortex and ventricles. Alternatively, organoid models cannot completely replicate certain specific stages of brain development, such as brain surface folding and complex neuronal circuitry establishment. Nevertheless, few advancements to improve organoid systems and mimic embryonic human brain complexities have been reported. These include sophisticated culture protocol establishment, brain organoid vascularization and transplantation, regionalized brain organoid assembly into relatively complete brain organoids (e.g., assembloids). In general, recent advancements in brain organoid technology have demonstrated significant potential for advancing regenerative medicine, drug discovery, and disease modeling.
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Application of brain organoids in neurodevelopmental disorders.
Understanding the etiology of human neurological and psychiatric disorders remains challenging due to species-specific genomic architectures, prolonged developmental timelines, and the unique cytoarchitectural features of the human brain, which are inadequately replicated in conventional animal models. To address these limitations, human pluripotent stem cell (hPSC)-derived brain organoids have emerged as an ethically accessible experimental system that recapitulates critical aspects of early human neurodevelopment in vitro. These three-dimensional (3D) models mimic the generation of neural progenitors, their proliferation and differentiation into neurons and glial cells, as well as the dynamic cell-cell interactions that govern cortical lamination and circuit assembly. Recent advancements in organoid culture protocols-including the fusion of region-specific brain organoids, vascularization strategies, and the incorporation of microglia-have yielded more physiologically relevant models. Such innovations enable the development of powerful bioassays to investigate disease mechanisms underlying neurodevelopmental disorders (NDDs). Despite persistent challenges related to functional synaptic maturation and modeling the blood-brain barrier, the integration of single-cell multiomics,organoid-on-a-chip systems,and xenotransplantation approaches holds promise for unraveling human-specific pathophysiology and accelerating therapeutic discovery.This review synthesizes the progress in brain organoid technologies and highlights their potential to deepen mechanistic insights into brain disorders while advancing translational research.
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Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease.
Understanding etiology of human neurological and psychiatric diseases is challenging. Genomic changes, protracted development, and histological features unique to human brain development limit the disease aspects that can be investigated using model organisms. Hence, in order to study phenotypes associated with human brain development, function, and disease, it is necessary to use alternative experimental systems that are accessible, ethically justified, and replicate human context. Human pluripotent stem cell (hPSC)-derived brain organoids offer such a system, which recapitulates features of early human neurodevelopment in vitro, including the generation, proliferation, and differentiation of neural progenitors into neurons and glial cells and the complex interactions among the diverse, emergent cell types of the developing brain in three-dimensions (3-D). In recent years, numerous brain organoid protocols and related techniques have been developed to recapitulate aspects of embryonic and fetal brain development in a reproducible and predictable manner. Altogether, these different organoid technologies provide distinct bioassays to unravel novel, disease-associated phenotypes and mechanisms. In this review, we summarize how the diverse brain organoid methods can be utilized to enhance our understanding of brain disorders. FACTS: Brain organoids offer an in vitro approach to study aspects of human brain development and disease. Diverse brain organoid techniques offer bioassays to investigate new phenotypes associated with human brain disorders that are difficult to study in monolayer cultures. Brain organoids have been particularly useful to study phenomena and diseases associated with neural progenitor morphology, survival, proliferation, and differentiation. OPEN QUESTION: Future brain organoid research needs to aim at later stages of neurodevelopment, linked with neuronal activity and connections, to unravel further disease-associated phenotypes. Continued improvement of existing organoid protocols is required to generate standardized methods that recapitulate in vivo-like spatial diversity and complexity.
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Brain Organoids: A Promising Living Biobank Resource for Neuroscience Research.
Biobanking plays an important role between clinical practice and translational research. In addition to the traditional biomolecular-based biobanks, there is a growing interest in establishing living biobanks, including organoid biobanks that can collect and store viable and functional tissues and proliferative cell types for long periods of time. An organoid is a three-dimensional cell complex derived by self-organization of small tissue blocks or stem cells, which can recapitulate the phenotypic and genetic characteristics of targeted human organs. Publications on brain organoids have increased recently, and several types of brain organoids have been reported to model normal and abnormal neural development, as well as different neurodegenerative diseases, neuropsychiatric disorders, and other neural conditions. Based on the current status of research, more exploration on brain organoids is needed, through technical advancements, to improve the reproducibility and scalability, as well as to decrease the diversity. Moreover, given their natural characteristics, more attention to ethical considerations is needed, considering the extent of maturation and complexity of brain organoids. Living biobanks that are engaged in collecting categories of brain organoids possessing different genetic backgrounds, and with spatial and temporal characteristics, will eventually contribute to the understanding of neural conditions and ultimately facilitate innovative treatment development.