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Learning about cell lineage, cellular diversity and evolution of the human brain through stem cell models.
Here, we summarize the current knowledge on cell diversity in the cortex and other brain regions from in vivo mouse models and in vitro models based on pluripotent stem cells. We discuss the mechanisms underlying cell proliferation and temporal progression that leads to the sequential generation of neurons dedicated to different layers of the cortex. We highlight models of corticogenesis from stem cells that recapitulate specific transcriptional and connectivity patterns from different cortical areas. We overview state-of-the art of human brain organoids modeling different brain regions, and we discuss insights into human cortical evolution from stem cells. Finally, we interrogate human brain organoid models for their competence to recapitulate the essence of human brain development.
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CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening.
The paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.
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A Static Self-Directed Method for Generating Brain Organoids from Human Embryonic Stem Cells.
Human brain organoids differentiated from embryonic stem cells offer the unique opportunity to study complicated interactions of multiple cell types in a three-dimensional system. Here we present a relatively straightforward and inexpensive method that yields brain organoids. In this protocol human pluripotent stem cells are broken into small clusters instead of single cells and grown in basic media without a heterologous basement membrane matrix or exogenous growth factors, allowing the intrinsic developmental cues to shape the organoid's growth. This simple system produces a diversity of brain cell types including glial and microglial cells, stem cells, and neurons of the forebrain, midbrain, and hindbrain. Organoids generated from this protocol also display hallmarks of appropriate temporal and spatial organization demonstrated by brightfield images, histology, immunofluorescence and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Because these organoids contain cell types from various parts of the brain, they can be utilized for studying a multitude of diseases. For example, in a recent paper we demonstrated the use of organoids generated from this protocol for studying the effects of hypoxia on the human brain. This approach can be used to investigate an array of otherwise difficult to study conditions such as neurodevelopmental handicaps, genetic disorders, and neurologic diseases.
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Evidences of neurological injury caused by COVID-19 from glioma tissues and glioma organoids.
INTRODUCTION: Despite the extensive neurological symptoms induced by COVID-19 and the identification of SARS-CoV-2 in post-mortem brain samples from COVID-19 patients months after death, the precise mechanisms of SARS-CoV-2 invasion into the central nervous system remain unclear due to the lack of research models. METHODS: We collected glioma tissue samples from glioma patients who had a recent history of COVID-19 and examined the presence of the SARS-CoV-2 spike protein. Subsequently, spatial transcriptomic analyses were conducted on normal brain tissues, glioma tissues, and glioma tissues from glioma patients with recent COVID-19 history. Additionally, single-cell sequencing data from both glioma tissues and glioma organoids were collected and analyzed. Glioma organoids were utilized to evaluate the efficacy of potential COVID-19 blocking agents. RESULTS: Glioma tissues from glioma patients with recent COVID-19 history exhibited the presence of the SARS-CoV-2 spike protein. Differences between glioma tissues from glioma patients who had a recent history of COVID-19 and healthy brain tissues primarily manifested in neuronal cells. Notably, neuronal cells within glioma tissues of COVID-19 history demonstrated heightened susceptibility to Alzheimer's disease, depression, and synaptic dysfunction, indicative of neuronal aberrations. Expressions of SARS-CoV-2 entry factors were confirmed in both glioma tissues and glioma organoids. Moreover, glioma organoids were susceptible to pseudo-SARS-CoV-2 infection and the infections could be partly blocked by the potential COVID-19 drugs. CONCLUSIONS: Gliomas had inherent traits that render them susceptible to SARS-CoV-2 infection, leading to their representability of COVID-19 neurological symptoms. This established a biological foundation for the rationality and feasibility of utilization of glioma organoids as research and blocking drug testing model in SARS-CoV-2 infection within the central nervous system.
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Patient-Derived PSEN1 Cerebral Organoids Revealed Parallel Development of Amyloid-β Accumulation and Network Dysfunction.
Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-β (Aβ) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated Aβ42/40 and Aβ aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that Aβ dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential Aβ-induced changes in excitability during the preclinical stages of AD.
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Advances in human cellular mechanistic understanding and drug discovery of brain organoids for neurodegenerative diseases.
The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.
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Vascularised Brain Organoids: Engineering Strategies and Neurobiological Applications.
Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This deficiency restricts organoid size, contributes to necrotic core formation, and hampers their functional maturation. Introducing vascularization offers a compelling solution-it enhances nutrient delivery, supports neurogenesis, and fosters the development of interfaces that resemble the blood-brain barrier (BBB). In this review, we explore how vascularization enhances the structural and physiological relevance of brain organoids and its growing significance in disease modelling and therapeutic screening. We examine current methodologies for engineering vascularized brain organoids (vBOs), including co-culturing with endothelial cells (ECs), transcriptional programming, tissue fusion techniques, microfluidic perfusion systems, and 3D bioprinting. These strategies vary in complexity, scalability, and the extent to which they achieve vascular integration. Functionally, vBOs demonstrate improved oxygen diffusion, enhanced synaptic development, and more robust barrier properties. Such advances enable modelling of complex neurovascular conditions like stroke, glioblastoma, and BBB dysfunction. Moreover, vBOs are emerging as valuable tools in developmental studies and personalised medicine, supporting patient-derived modelling and large-scale drug testing in BBB-relevant contexts. Despite these advances, replicating the structural complexity, functionality, and long-term stability of native vasculature remains challenging. We discuss current limitations and highlight innovative approaches, including the use of next-generation biomaterials and dynamic perfusion technologies. Ultimately, vBOs mark a significant step towards creating physiologically accurate in vitro models of the human brain-offering new opportunities for neuroscience research, drug development, and regenerative medicine.
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Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single-cell resolution.
Dissecting human neurobiology at high resolution and with mechanistic precision requires a major leap in scalability, given the need for experimental designs that include multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we have developed and benchmarked complementary strategies to multiplex brain organoids by pooling cells from different pluripotent stem cell (PSC) lines either during organoid generation (mosaic models) or before single-cell RNA sequencing (scRNA-seq) library preparation (downstream multiplexing). We have also developed a new computational method, SCanSNP, and a consensus call to deconvolve cell identities, overcoming current criticalities in doublets and low-quality cell identification. We validated both multiplexing methods for charting neurodevelopmental trajectories at high resolution, thus linking specific individuals' trajectories to genetic variation. Finally, we modeled their scalability across different multiplexing combinations and showed that mosaic organoids represent an enabling method for high-throughput settings. Together, this multiplexing suite of experimental and computational methods provides a highly scalable resource for brain disease and neurodiversity modeling.
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An in vivo model of functional and vascularized human brain organoids.
Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.
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Human Cerebral Organoids Reveal Early Spatiotemporal Dynamics and Pharmacological Responses of UBE3A.
Angelman syndrome is a complex neurodevelopmental disorder characterized by delayed development, intellectual disability, speech impairment, and ataxia. It results from the loss of UBE3A protein, an E3 ubiquitin ligase, in neurons of the brain. Despite the dynamic spatiotemporal expression of UBE3A observed in rodents and the potential clinical importance of when and where it is expressed, its expression pattern in humans remains unknown. This reflects a common challenge of studying human neurodevelopment: prenatal periods are hard to access experimentally. In this work, human cerebral organoids reveal a change from weak to strong UBE3A in neuronal nuclei within 3 weeks of culture. Angelman syndrome human induced pluripotent stem cell-derived organoids also exhibit early silencing of paternal UBE3A, with topoisomerase inhibitors partially rescuing UBE3A levels and calcium transient phenotypes. This work establishes human cerebral organoids as an important model for studying UBE3A and motivates their broader use in understanding complex neurodevelopmental disorders.