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Vascularized human brain organoid on-chip.
Modelling the human brain in vitro has been extremely challenging due to the brain's intricate cellular composition and specific structural architecture. The recent emergence of brain organoids that recapitulate many key features of human brain development has thus piqued the interest of many to further develop and apply this in vitro model for various physiological and pathological investigations. Despite ongoing efforts, the existing brain organoids demonstrate several limitations, such as the lack of a functional human vasculature with perfusion capability. Microfluidics is suited to enhance such brain organoid models by enabling vascular perfusion and a curated blood-brain barrier microenvironment. In this review, we first provide an introduction to in vivo human brain development and present the state-of-the-art in vitro human brain models. We further elaborate on different strategies to improve the vascularized human brain organoid microenvironment using microfluidic devices, while discussing the current obstacles and future directions in this field.
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Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) are mitochondrial disorders most commonly caused by a m.3243A>G variant in mitochondrial tRNALeu. To investigate the pathophysiology of MELAS, we generated brain organoids from multiple induced pluripotent stem cell (iPSC) lines derived from a patient with MELAS carrying the m.3243A>G variant. These lines share an identical nuclear genetic background but differ in their heteroplasmy levels involving the m.3243A>G variant. We observed significant differences in organoid size, morphology, and neural induction efficiency, which correlated with the degree of heteroplasmy. Dissociated neurons from the organoids were transferred into a 2D-culture system, which is convenient and suitable for high-throughput drug screening. The organoids also exhibited significant differences in the formation of neural networks, depending on heteroplasmy levels. Our results suggest that patient-derived iPSC-based organoid models represent a useful platform for studying MELAS mechanisms and for drug screening. This video presents comprehensive and user-friendly methods, including protocols for generating organoids and evaluating phenotypes.
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Modeling sporadic Alzheimer's disease using brain organoids: Emerging trends and translational opportunities.
Sporadic form of Alzheimer's disease (sAD), remains a complex neurodegenerative disorder with limited translational models. Brain organoids derived from human induced pluripotent stem cells (hiPSCs) have emerged as promising tools to recapitulate aspects of human brain development and pathology. Recent advances have introduced vascularized, immune-competent organoids capable of modeling hallmark features of sAD, including amyloid-β accumulation, tau pathology, and neuroinflammation. New strategies to enhance organoid maturation, cellular diversity, and aging phenotypes are pushing the boundaries of disease modeling. This review highlights cutting-edge developments in brain organoid systems for studying sAD, addresses key limitations, and outlines future directions to improve their translational relevance for therapy and mechanistic insights.
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Advances in hiPSC-Derived Brain Organoids as a Model to Study Neuroinflammation in Alzheimer's Disease.
Neuroinflammation plays a fundamental role in several neurodegenerative diseases, including Alzheimer's disease (AD), the leading cause of dementia worldwide. As the main defense response of the central nervous system (CNS), neuroinflammation can be either protective or detrimental depending on the stage of the disease. The pivotal role of neuroinflammation in AD has led to increasing investigations into neuroinflammatory mechanisms, aiming to develop AD-modifying therapies. A significant advance in the field was the emergence of the human induced pluripotent stem cell (hiPSC) model, enabling the study of patient-derived cells. Moreover, the development of hiPSC-derived brain organoids, which mimic specific aspects of the human CNS, has expanded our understanding of neuroinflammation in AD. Here, we review how AD organoid models have evolved, focusing on the integration of microglia-the brain's primary immune surveillance cells. We also summarize recent findings on how glial activation and the crosstalk between microglia and other CNS cells affect AD progression. Lastly, we address the potential of hiPSC-derived organoids as a preclinical model for screening AD drugs.
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Can We Better Understand How Zika Leads to Microcephaly? A Systematic Review of the Effects of the Zika Virus on Human Brain Organoids.
BACKGROUND: The innovative human brain organoid model represents a unique opportunity to better understand the genesis of congenital brain abnormalities, particularly microcephaly, caused by Zika virus (ZIKV) infection during early pregnancy. METHODS: A systematic review was conducted to investigate how ZIKV leads to microcephaly in a novel experimental model that mimics early brain development. Studies were gathered by searching MEDLINE/Pubmed, LILACS, and LiSSa for reports on effects of ZIKV infection on human brain organoids. From 146 identified papers, 13 articles were selected for review. RESULTS: This review found that ZIKV of African, Latin American, and Asian lineages caused productive replication after 72 hours, preferentially infected neural progenitor cells over mature neurons, reduced both cell populations, and caused premature differentiation. Limited data involving only African and Latin American lineages showed a reduction in populations of proliferating cells and intermediate cells, and overall decreased viability. Furthermore, all 3 lineages caused heightened apoptosis and reduced organoid size. CONCLUSIONS: This review concludes that, in organoids, ZIKV causes productive replication, infects neural progenitor cells over mature neurons, decreases both populations, causes premature differentiation, induces apoptosis, and reduces size.
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Exploring landscapes of brain morphogenesis with organoids.
The field of developmental neuroscience is benefitting from recent technological advances that allow access to organogenesis in vitro via organoid preparations. These methods have been applied to better understanding neural identity, and have opened up a window into the early events that occur during development of the human brain. However, current approaches are not without their limitations, and although brain organoids and other in vitro paradigms recapitulate many processes with remarkable fidelity, there are clear differences between brain organoid development in vitro and brain development in vivo These topics were discussed extensively at a recent workshop organized by The Company of Biologists entitled 'Thinking beyond the dish: taking in vitro neural differentiation to the next level'. Here, we summarize the common themes that emerged from the workshop and highlight some of the limitations and the potential of this emerging technology. In particular, we discuss how organoids can help us understand not only healthy and diseased brain, but also explore new arrays of cellular behaviors.
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Consciousness and Human Brain Organoids: A Conceptual Mapping of Ethical and Philosophical Literature.
Human brain organoids (HBOs) are three-dimensional structures derived from human pluripotent stem cells that model aspects of fetal brain development. As HBO models grow more complex, ethical concerns arise, particularly around the potential for consciousness. Defining and detecting consciousness in HBOs remains unresolved, with existing theories offering conflicting predictions. This systematic review examines how consciousness is conceptualized in the ethical and philosophical literature concerning HBOs. We selected peer-reviewed publications written in English from 2013 onward that directly address consciousness regarding HBOs. After screening 51 sources, 24 were analysed in themes: Consciousness Terminology, Biological Limitations, Theories of Consciousness, Detecting Consciousness, Comparisons with Conscious Entities, and Special Entities. Uncertainty about consciousness in general complicates the conversation around HBOs. Clear communication is essential to avoid misconceptions, and future research may benefit from focusing on organoid intelligence as a more tractable concept.
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Vascularized human brain organoids as a model of the brain-peripheral axis in HIV-1 neuropathogenesis.
Advances in stem cell biology and tissue engineering have enabled the generation of brain organoids from human induced pluripotent stem cells (hiPSCs), providing powerful platforms to model human brain development and neurodegenerative diseases. However, the lack of vascularization in conventional brain organoids limits nutrient and oxygen diffusion, thereby constraining their viability and physiological relevance. To overcome this limitation, we developed vascularized brain organoids using both normal hiPSCs and hiPSCs overexpressing the endothelial transcription factor ETS variant 2 (ETV2). Furthermore, this model also provides a unique opportunity to investigate how HIV-1 disrupts endothelial integrity within the CNS. Organoids were generated through co-culture differentiation using a modified protocol optimized to promote vascularization. Following characterization, organoids were exposed to HIV-1-infected PMPs in the presence or absence of ART. Viral replication was quantified using p24 ELISA and qRT-PCR assays. Our findings demonstrate the successful development of vascularized brain organoids (EndohBOs), which exhibit robust expression of CD31, Collagen IV, and GFAP footing, recapitulating key structural and cellular components of the human neurovascular unit. Notably, EndohBOs supported a higher number of transmigrated HIV-1-infected Primitive macrophage progenitor cells or Monocytes (PMPs) as evidenced by imaging. Interestingly, Antiretroviral therapy (ART) treatment failed to substantially reduce viral RNA or p24 levels, suggesting that despite ART exposure, viral replication persisted within EndohBOs. Overall, this vascularized brain organoid model provides a physiologically relevant human system to study the effects of HIV-1 and other neurotropic pathogens on the CNS. It also offers a promising platform for testing CNS-targeted therapeutic interventions aimed at restoring neurovascular integrity and mitigating HIV-induced barrier disruption.
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Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.
INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses. METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects. RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity. DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.
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In Vitro Brain Organoids and Computational Models to Study Cell Death in Brain Diseases.
Understanding the mechanisms underlying the formation and progression of brain diseases is challenging due to the vast variety of involved genetic/epigenetic factors and the complexity of the environment of the brain. Current preclinical monolayer culture systems fail to faithfully recapitulate the in vivo complexities of the brain. Organoids are three-dimensional (3D) culture systems that mimic much of the complexities of the brain including cell-cell and cell-matrix interactions. Complemented with a theoretical framework to model the dynamic interactions between different components of the brain, organoids can be used as a potential tool for studying disease progression, transport of therapeutic agents in tissues, drug screening, and toxicity analysis. In this chapter, we first report on the fabrication and use of a novel self-filling microwell arrays (SFMWs) platform that is self-filling and enables the formation of organoids with uniform size distributions. Next, we will introduce a mathematical framework that predicts the organoid growth, cell death, and the therapeutic responses of the organoids to different therapeutic agents. Through systematic investigations, the computational model can identify shortcomings of in vitro assays and reduce the time and effort required to improve preclinical tumor models' design. Lastly, the mathematical model provides new testable hypotheses and encourages mathematically driven experiments.