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The Emergence of Stem Cell-Based Brain Organoids: Trends and Challenges.
Recent developments in 3D cultures exploiting the self-organization ability of pluripotent stem cells have enabled the generation of powerful in vitro systems termed brain organoids. These 3D tissues recapitulate many aspects of human brain development and disorders occurring in vivo. When combined with improved differentiation methods, these in vitro systems allow the generation of more complex "assembloids," which are able to reveal cell diversities, microcircuits, and cell-cell interactions within their 3D organization. Here, the ways in which human brain organoids have contributed to demystifying the complexities of brain development and modeling of developmental disorders is reviewed and discussed. Furthermore, challenging questions that are yet to be addressed by emerging brain organoid research are discussed.
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A Little Bit of Guidance: Mini Brains on Their Route to Adolescence.
Cerebral organoids represent a new model in which to study human brain development outside the human body. Recently in Nature Biotechnology, Lancaster et al. (2017) tackled the lack of reproducibility, tissue homogeneity, and complexity of this system by bioengineering organoids to establish the next generation of human mini brains.
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Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus.
Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.
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The boom in mini stomachs, brains, breasts, kidneys and more.
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Back to the origins: Human brain organoids to investigate neurodegeneration.
Neurodegenerative disorders represent a high burden in terms of individual, social and economical resources. No ultimate therapy has been established so far; human brain morphology and development can not be entirely reproduced by animal models, and genomic, metabolic and biochemical differences might contribute to a limited predictive power for human translation. Thus, the development of human brain organoid models holds a wide potential to investigate the range of physiological and pathological features that characterise the early onset of the degeneration. Moreover, central nervous system development has gained a crucial role in the study of the pathogenesis of neurodegenerative disorders. Premature alterations during brain maturation have been related to late disease manifestations; genetic mutations responsible for neurodegeneration have been found in genes highly expressed during neural development. Elucidating the mechanisms triggering neuronal susceptibility to degeneration is crucial for pathogenetic studies and therapeutic discoveries. In the present work, we provide an overview on the current applications of human brain organoids towards studies of neurodegenerative diseases, with a survey on the recent discoveries and a closing discussion on the present challenges and future perspectives.
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Establishing mouse forebrain organoids as models of intrinsic cortical network assembly.
The mouse cortex is a canonical model for studying how functional neural networks emerge, yet it remains unclear which topological features arise from intrinsic cellular organization versus sensory input. Mouse forebrain organoids provide a powerful system to investigate these intrinsic mechanisms. We generated dorsal (DF) and ventral (VF) forebrain organoids from mouse pluripotent stem cells and tracked their development using longitudinal electrophysiology. DF organoids showed progressively stronger network-wide correlations, while VF organoids developed more refined activity patterns with enhanced small-world topology and increased modular organization. Both organoid types form small-world networks, but their topological organization differs. These differences emerge without extrinsic inputs and correlate with Pvalb+ interneuron enrichment in VF organoids. Our findings demonstrate how cellular composition influences neural circuit self-organization, establishing mouse forebrain organoids as a tractable platform to study cortical network architecture.
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Antidepressant aripiprazole induces adverse effects on neural development during cortex organoid generation.
A significant number of women experience anxiety and depressive symptoms during pregnancy, leading to the prescription of antidepressants, including aripiprazole. However, although a few animal studies have reported its developmental toxicity, there is a lack of research on the potential risks aripiprazole may pose to the fetus, particularly regarding neural development, as well as an absence of appropriate models to verify these effects. Therefore, this study investigates the impact of aripiprazole on neural development using cortex organoids, which can effectively model human brain development and function while overcoming interspecies differences. Cortex organoids were generated and exposed to aripiprazole at concentrations of 0.3-9 µM over 4 weeks. We assessed morphological changes, cell viability, gene expression, immunofluorescence staining, and electrophysiological function. The results revealed that aripiprazole led to significant reductions in organoid size and increased cell death, particularly at higher concentrations. Immunofluorescence analysis showed abnormalities in the expression patterns of neural stem cells and neuronal markers. Additionally, real-time PCR demonstrated decreased expression of genes related to neural stem cells, neural differentiation and migration, maturation, synaptogenesis, and gliogenesis, along with increased apoptosis-related gene expression. Electrophysiological recordings indicated impaired neural activity, evidenced by reduced mean firing rates. Our study is the first to demonstrate that aripiprazole induces adverse effects on neural development across functional, molecular, and morphological aspects. The findings will aid in a better understanding of the risks associated with antidepressant use during pregnancy in terms of neural development and suggest that cortex organoids are a valuable model for evaluating potential neurodevelopmental toxicants.
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Recapitulating influenza virus infection and facilitating antiviral and neuroprotective screening in tractable brain organoids.
Human pluripotent stem cell derived brain organoids offer an unprecedented opportunity for various applications as in vitro model. Currently, human brain organoids as models have been used to understand virus-induced neurotoxicity. Methods: The brain organoids were separately challenged by multiple viruses including influenza viruses (H1N1-WSN and H3N2-HKT68), Enteroviruses (EV68 and EV71) and Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) to investigate the impaired effect of these viruses on human brain development. Results: The brain organoids challenged by influenza viruses had decreased overall organoid size, while enteroviruses infected brain organoids displayed the opposite result. Then, we found WSN preferentially infected MAP2+ neurons compared to SOX2+ neural stem cells (NSCs) and GFAP+ astrocytes in brain organoids, and induced apoptosis of NSCs and neurons, and released inflammatory factors (TNF-α, INF-γ, and IL-6), facilitating brain damage. Furthermore, transcriptional profiling revealed several co-upregulated genes (CSAG3 and OAS2) and co-downregulated genes (CDC20B, KCNJ13, OTX2-AS1) after WSN infection for 24 hpi and 96 hpi, implicating target for antiviral drugs development. Finally, we explored compound PYC-12 could significantly suppress virus infection, apoptosis, and inflammatory responses. Conclusions: Collectively, we established a tractable experimental model to investigate the impact and mechanism of virus infection on human brain development.
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Benzo[a]pyrene-induced AHR activation in human ESCs primes premature neurogenesis in cerebral organoids.
Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon (PAH), is a widespread environmental toxicant and potent ligand of the aryl hydrocarbon receptor (AHR). Yet, how early developmental exposure to BaP influences human neurodevelopment remains poorly understood. To identify an appropriate exposure window, we characterized AHR expression during human embryonic stem cell (ESC)-derived cerebral organoid development and observed the highest expression at the ESC stage, followed by a decline during subsequent differentiation, highlighting the ESC stage as a potentially vulnerable stage for AHR-mediated environmental perturbation. Based on this observation, ESCs were exposed to BaP (0.1, 1 μM) for 7 days prior to organoid generation. BaP exposure did not alter pluripotency, proliferation, cell death, or global transcription of ESCs but increased expression of a subset of AHR target genes. Remarkably, however, organoids derived from BaP-exposed ESCs exhibited profound morphological defects resulting from premature neurogenesis, characterized by disrupted neural rosette organization, reduced EOMES⁺ intermediate progenitors, and increased BCL11B⁺ neurons. Pharmacological inhibition of AHR with CH-223191 attenuated AHR activation and rescued the progenitor-neuron imbalance. These findings identify AHR signaling as a critical upstream mediator of BaP-induced developmental neurotoxicity and highlight the vulnerability of early pluripotent stages to environmental insults.
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From Cell Culture to Organoids-Model Systems for Investigating Prion Strain Characteristics.
Prion diseases are the hallmark protein folding neurodegenerative disease. Their transmissible nature has allowed for the development of many different cellular models of disease where prion propagation and sometimes pathology can be induced. This review examines the range of simple cell cultures to more complex neurospheres, organoid, and organotypic slice cultures that have been used to study prion disease pathogenesis and to test therapeutics. We highlight the advantages and disadvantages of each system, giving special consideration to the importance of strains when choosing a model and when interpreting results, as not all systems propagate all strains, and in some cases, the technique used, or treatment applied, can alter the very strain properties being studied.