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Development and Application of Brain Region-Specific Organoids for Investigating Psychiatric Disorders.
Human society has been burdened by psychiatric disorders throughout the course of its history. The emergence and rapid advances of human brain organoid technology provide unprecedented opportunities for investigation of potential disease mechanisms and development of targeted or even personalized treatments for various psychiatric disorders. In this review, we summarize recent advances for generating organoids from human pluripotent stem cells to model distinct brain regions and diverse cell types. We also highlight recent progress, discuss limitations, and propose potential improvements in using patient-derived or genetically engineered brain region-specific organoids for investigating various psychiatric disorders.
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Brain organoids: the quest to decipher human-specific features of brain development.
The development of the human brain occurs largely in utero over long periods of time and is thus experimentally inaccessible; therefore, tractable experimental models are needed. Human brain organoid have emerged as powerful model systems to investigate human-specific features of brain development. Focusing on the cerebral cortex, here, we discuss how brain, and more specifically cortical, organoid models have newly enabled discovery of aspects of progenitor biology and cortical-cell diversification that are unique to humans. We foresee that as advancements in organoid generation increase the complexity of these models, more complete replicas of the brain will empower future studies investigating higher-order aspects of brain biology, toward an understanding of the unique processing capabilities of the human brain.
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Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation.
Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures. This method leads to sustained neurogenesis and formation of an expanded cortical plate that establishes distinct upper and deep cortical layers for neurons and astrocytes, resembling the third trimester embryonic human neocortex. Using the SNO system, we further identify a critical role of WNT/β-catenin signaling in regulating human cortical neuron subtype fate specification, which is disrupted by a psychiatric-disorder-associated genetic mutation in patient induced pluripotent stem cell (iPSC)-derived SNOs. These results demonstrate the utility of SNOs for investigating previously inaccessible human-specific, late-stage cortical development and disease-relevant mechanisms.
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Human Brain Organoids as an In Vitro Model System of Viral Infectious Diseases.
Brain organoids, or brainoids, have shown great promise in the study of central nervous system (CNS) infection. Modeling Zika virus (ZIKV) infection in brain organoids may help elucidate the relationship between ZIKV infection and microcephaly. Brain organoids have been used to study the pathogenesis of SARS-CoV-2, human immunodeficiency virus (HIV), HSV-1, and other viral infections of the CNS. In this review, we summarize the advances in the development of viral infection models in brain organoids and their potential application for exploring mechanisms of viral infections of the CNS and in new drug development. The existing limitations are further discussed and the prospects for the development and application of brain organs are prospected.
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Brain Chimeroids reveal individual susceptibility to neurotoxic triggers.
Interindividual genetic variation affects the susceptibility to and progression of many diseases1,2. However, efforts to study how individual human brains differ in normal development and disease phenotypes are limited by the paucity of faithful cellular human models, and the difficulty of scaling current systems to represent multiple people. Here we present human brain Chimeroids, a highly reproducible, multidonor human brain cortical organoid model generated by the co-development of cells from a panel of individual donors in a single organoid. By reaggregating cells from multiple single-donor organoids at the neural stem cell or neural progenitor cell stage, we generate Chimeroids in which each donor produces all cell lineages of the cerebral cortex, even when using pluripotent stem cell lines with notable growth biases. We used Chimeroids to investigate interindividual variation in the susceptibility to neurotoxic triggers that exhibit high clinical phenotypic variability: ethanol and the antiepileptic drug valproic acid. Individual donors varied in both the penetrance of the effect on target cell types, and the molecular phenotype within each affected cell type. Our results suggest that human genetic background may be an important mediator of neurotoxin susceptibility and introduce Chimeroids as a scalable system for high-throughput investigation of interindividual variation in processes of brain development and disease.
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Shaping the Neurovascular Unit Exploiting Human Brain Organoids.
Brain organoids, three-dimensional cell structures derived from pluripotent stem cells, closely mimic key aspects of the human brain in vitro, providing a powerful tool for studying neurodevelopment and disease. The neuroectodermal induction protocol employed for brain organoid generation primarily gives rise to the neural cellular component but lacks the vital vascular system, which is crucial for the brain functions by regulating differentiation, migration, and circuit formation, as well as delivering oxygen and nutrients. Many neurological diseases are caused by dysfunctions of cerebral microcirculation, making vascularization of human brain organoids an important tool for pathogenetic and translational research. Experimentally, the creation of vascularized brain organoids has primarily focused on the fusion of vascular and brain organoids, on organoid transplantation in vivo, and on the use of microfluidic devices to replicate the intricate microenvironment of the human brain in vitro. This review summarizes these efforts and highlights the importance of studying the neurovascular unit in a forward-looking perspective of leveraging their use for understanding and treating neurological disorders.
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Brain Organoids: Tools for Understanding the Uniqueness and Individual Variability of the Human Brain.
Understanding the drivers of human brain specialization, and how specialized properties are codified during development and evolution, seems to be within reach for the first time. Improved cell-based experimental models of the human brain have empowered the field to address some of the most fundamental questions about our brains, including mechanisms of neurodevelopment, the etiology of neurological disease, and the underpinnings of human-to-human variation in brain function and response. The emergence of scalable in vitro systems has enabled investigation of interindividual variation within large human cohorts in both normal development and disease processes, which is fundamental to developing effective and personalized treatments. This review explores recent advancements in organoid technology, highlighting future directions that employ interdisciplinary approaches to enhance the physiological relevance of these models. This work promises to bring us ever closer to understanding not only what makes a brain human but also how each of our brains is human in unique ways.
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Cultures and cures: neurodiversity and brain organoids.
BACKGROUND: Research with cerebral organoids is beginning to make significant progress in understanding the etiology of autism spectrum disorder (ASD). Brain organoid models can be grown from the cells of donors with ASD. Researchers can explore the genetic, developmental, and other factors that may give rise to the varieties of autism. Researchers could study all of these factors together with brain organoids grown from cells originating from ASD individuals. This makes brain organoids unique from other forms of ASD research. They are like a multi-tool, one with significant versatility for the scope of ASD research and clinical applications. There is hope that brain organoids could one day be used for precision medicine, like developing tailored ASD drug treatments. MAIN BODY: Brain organoid researchers often incorporate the medical model of disability when researching the origins of ASD, especially when the research has the specific aim of potentially finding tailored clinical treatments for ASD individuals. The neurodiversity movement-a developmental disability movement and paradigm that understands autism as a form of natural human diversity-will potentially disagree with approaches or aims of cerebral organoid research on ASD. Neurodiversity advocates incorporate a social model of disability into their movement, which focuses more on the social, attitudinal, and environmental barriers rather than biophysical or psychological deficits. Therefore, a potential conflict may arise between these perspectives on how to proceed with cerebral organoid research regarding neurodevelopmental conditions, especially ASD. CONCLUSIONS: Here, we present these perspectives and give at least three initial recommendations to achieve a more holistic and inclusive approach to cerebral organoid research on ASD. These three initial starting points can build bridges between researchers and the neurodiversity movement. First, neurodiverse individuals should be included as co-creators in both the scientific process and research communication. Second, clinicians and neurodiverse communities should have open and respectful communication. Finally, we suggest a continual reconceptualization of illness, impairment, disability, behavior, and person.
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Single-cell transcriptomics of vascularized human brain organoids decipher lineage-specific stress adaptation in fetal hypoxia-reoxygenation injury.
Rationale: Fetal hypoxia, a major contributor to neonatal mortality, induces complex neurovascular disruptions in developing brains, yet human-specific cellular mechanisms remain poorly understood due to limitations in existing models. This study establishes an advanced vascularized human cortical organoid (vhCO) model to decode cell type-specific injury mechanisms and therapeutic targets during hypoxia-reoxygenation. Methods: We developed vhCOs by integrating cortical and vascular organoids, recapitulating mid-to-late gestational neurodevelopment with diverse lineages-neural progenitors, neurons, microglia, and functional vasculature with blood-brain barrier properties. Hypoxia-reoxygenation experiments were conducted on vhCOs, followed by single-cell transcriptomic profiling to dissect cellular responses. Results: Key findings include: (1) Lineage-specific vulnerabilities: astrocyte precursors exhibited developmental arrest, while immature GABAergic neurons (Subtype I) underwent neurogenic collapse. Microglia displayed a biphasic inflammatory response-initially suppressed, then hyperactivated post-reoxygenation, diverging from animal models; (2) Hypoxia memory persisted in non-neural cells (pericytes, fibroblasts), driving compartment-specific vascular remodeling via Notch signaling and collagen deposition; (3) Rewired neural-non-neural crosstalk networks (e.g., IGF2-IGF2R, LGALS3-MERTK, Wnts-SFRP2) revealed novel repair targets inaccessible to conventional models. Conclusions: By prioritizing single-cell resolution, this study delineates human-specific neurovascular pathophysiology and stress adaptation networks in hypoxic brain injury. The vhCO platform bridges translational gaps, offering a paradigm for precision therapeutics and advancing research on developmental brain disorders.
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Generation of human region-specific brain organoids with medullary spinal trigeminal nuclei.
Brain organoids with nucleus-specific identities provide unique platforms for studying human brain development and diseases at a finer resolution. Despite its essential role in vital body functions, the medulla of the hindbrain has seen a lack of in vitro models, let alone models resembling specific medullary nuclei, including the crucial spinal trigeminal nucleus (SpV) that relays peripheral sensory signals to the thalamus. Here, we report a method to differentiate human pluripotent stem cells into region-specific brain organoids resembling the dorsal domain of the medullary hindbrain. Importantly, organoids specifically recapitulated the development of the SpV derived from the dorsal medulla. We also developed an organoid system to create the trigeminothalamic projections between the SpV and the thalamus by fusing these organoids, namely human medullary SpV-like organoids (hmSpVOs), with organoids representing the thalamus (hThOs). Our study provides a platform for understanding SpV development, nucleus-based circuit organization, and related disorders in the human brain.