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Advancing Glioblastoma Research with Innovative Brain Organoid-Based Models.
Glioblastoma (GBM) is a relatively rare but highly aggressive form of brain cancer characterized by rapid growth, invasiveness, and resistance to standard therapies. Despite significant progress in understanding its molecular and cellular mechanisms, GBM remains one of the most challenging cancers to treat due to its high heterogeneity and complex tumor microenvironment. To address these obstacles, researchers have employed a range of models, including in vitro cell cultures and in vivo animal models, but these often fail to replicate the complexity of GBM. As a result, there has been a growing focus on refining these models by incorporating human-origin cells, along with advanced genetic techniques and stem cell-based bioengineering approaches. In this context, a variety of GBM models based on brain organoids were developed and confirmed to be clinically relevant and are contributing to the advancement of GBM research at the preclinical level. This review explores the preparation and use of brain organoid-based models to deepen our understanding of GBM biology and to explore novel therapeutic approaches. These innovative models hold significant promise for improving our ability to study this deadly cancer and for advancing the development of more effective treatments.
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Advances in Central Nervous System Organoids: A Focus on Organoid-Based Models for Motor Neuron Disease.
Despite their large societal burden, the development of therapeutic treatments for neurodegenerative diseases (NDDs) has been relatively unsuccessful. This is, in part, due to a lack of representative experimental models that reveal fundamental aspects of human brain pathology. Recently, assays for in vitro modeling of the human central nervous system (CNS) have significantly improved with the development of brain and spinal cord organoids. Coupled with induced-pluripotent stem cell and genome editing technologies, CNS organoids are a promising tool for studying neurodegeneration in a patient-specific manner. An extensive array of protocols for the generation of organoids for different brain regions has been developed and used for studying neurodegenerative and other brain diseases. However, their application in the field of motor neuron disease (MND) has been limited due to a lack of adequate organoid models. The development of protocols to derive spinal cord and trunk organoids and progress in the field of assembloids are providing new opportunities for modeling MND. In this study here we review recent advances in the development of CNS organoid models, their application in NDDs, and technical limitations. Finally, we discuss future perspectives for the development of organoid-based systems for MND and provide a framework for their development. Impact statement Animal models and two-dimensional cultures are currently the main platforms for studying neurodegenerative diseases (NDDs). However, central nervous system (CNS) organoid technology offers novel possibilities for studying these diseases. Organoid modeling in combination with emerging organ-on-a-chip approaches, induced-pluripotent stem cell technology, and genome editing render in vitro modeling of NDDs more robust and physiologically relevant. In this study, we review the principles underlying CNS organoid generation, their use in NDD research, and future perspectives in organoid technology. Finally, we discuss how advances in different fields could be combined to generate a multisystem organoid-on-a-chip model to investigate a specific class of NDDs, motor neuron diseases.
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Single-cell transcriptomics captures features of human midbrain development and dopamine neuron diversity in brain organoids.
Three-dimensional brain organoids have emerged as a valuable model system for studies of human brain development and pathology. Here we establish a midbrain organoid culture system to study the developmental trajectory from pluripotent stem cells to mature dopamine neurons. Using single cell RNA sequencing, we identify the presence of three molecularly distinct subtypes of human dopamine neurons with high similarity to those in developing and adult human midbrain. However, despite significant advancements in the field, the use of brain organoids can be limited by issues of reproducibility and incomplete maturation which was also observed in this study. We therefore designed bioengineered ventral midbrain organoids supported by recombinant spider-silk microfibers functionalized with full-length human laminin. We show that silk organoids reproduce key molecular aspects of dopamine neurogenesis and reduce inter-organoid variability in terms of cell type composition and dopamine neuron formation.
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Stimulus-Based ApoE Alzheimer's Disease Induction Model Using Microglia-Containing Brain Organoids for Drug Discovery.
Alzheimer's Disease (AD) is a multifaceted progressive neurodegenerative disease characterized by memory deficits and cognitive impairment. The disease is clinically diagnosed by the presence of β-amyloid (Aβ), hyperphosphorylated tau, and neurodegeneration. Animal models serve as an indispensable tool to understanding AD pathogenesis and evaluating potential therapeutic approaches. However, despite the development of more than 200 rodent models, species-specific differences limit the translational relevance. Brain organoids generated from induced pluripotent stem cells (iPSCs) have the potential to bridge the gap between transgenic mouse models and clinical trials in human patients. Herein, we describe a robust stimulus-based neuroimmune organoid model that demonstrates neuroinflammation, neurodegeneration, and lipid dysregulation with AD-relevant pathological markers. Using planar organoids containing neurons, astrocytes, microglia, and vascular cells, we performed in-depth characterization of the induced AD-like phenotype using supernatant proteomic analysis, immunofluorescence staining, NfL and GFAP release, scRNAseq, bulk RNAseq, and pathway analysis both acutely (24 h) and chronically (7 days). Furthermore, we show that the induced neuroinflammation, lipid dysregulation, and neurodegeneration can be ameliorated using small molecules. This defined inducible model system presents an opportunity for drug discovery and development using a complex multicellular brain microenvironment derived from human iPSCs.
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Protocol for differentiating human pluripotent stem cells into midbrain organoids for targeted microinjection of viruses.
Midbrain organoids serve as a valuable model for studying brain development and disease. Here, we present a viral infection protocol for midbrain organoid models. We describe steps for human pluripotent stem cell (hPSC) differentiation into midbrain organoids; equipment preparation; and targeted virus microinjection into organoids to reduce viral load, minimize cytotoxicity, and preserve structural integrity. We then detail procedures for visualizing infected cells. By combining the virus with specific promoters, this protocol enables precise targeting of tube-like ventricular zone (VZ) regions. For complete details on the use and execution of this protocol, please refer to Zhu et al.,1 Wu et al.,2 Xu et al.,3 and Lu et al.4.
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Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium.
Neurological complications are common in patients with COVID-19. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function is not well understood. Here, we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found that neurons and astrocytes were sparsely infected, but choroid plexus epithelial cells underwent robust infection. We optimized a protocol to generate choroid plexus organoids from hiPSCs and showed that productive SARS-CoV-2 infection of these organoids is associated with increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our findings provide evidence for selective SARS-CoV-2 neurotropism and support the use of hiPSC-derived brain organoids as a platform to investigate SARS-CoV-2 infection susceptibility of brain cells, mechanisms of virus-induced brain dysfunction, and treatment strategies.
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The promise of cerebral organoids for neonatology.
PURPOSE OF REVIEW: Applying discoveries from basic research to patients in the neonatal intensive care unit (NICU) is challenging given the difficulty of modeling this population in animal models, lack of translational relevance from animal models to humans, and scarcity of primary human tissue. Human cell-derived cerebral organoid models are an appealing way to address some of these gaps. In this review, we will touch on previous work to model neonatal conditions in cerebral organoids, some limitations of this approach, and recent strategies that have attempted to address these limitations. RECENT FINDINGS: While modeling of neurodevelopmental disorders has been an application of cerebral organoids since their initial description, recent studies have dramatically expanded the types of brain regions and disease models available. Additionally, work to increase the complexity of organoid models by including immune and vascular cells, as well as modeling human heterogeneity with mixed donor organoids will provide new opportunities to model neonatal pathologies. SUMMARY: Organoids are an attractive model to study human neurodevelopmental pathologies relevant to patients in the neonatal ICU. New technologies will broaden the applicability of these models to neonatal research and their usefulness as a drug screening platform.
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Clinically Amendable, Defined, and Rapid Induction of Human Brain Organoids from Induced Pluripotent Stem Cells.
Human brain organoids provide opportunities to produce three-dimensional (3D) brain-like tissues for biomedical research and translational drug discovery, toxicology, and tissue replacement. Here we describe a protocol for rapid and defined induction of brain organoids from human induced pluripotent stem cells (iPSCs), using commercially available culture and differentiation media and a cheap, easy to handle and clinically approved semisynthetic hydrogel. Importantly, the methodology is uncomplicated, well-defined, and reliable for reproducible and scalable organoid generation, and amendable to principles of current good laboratory practice (cGLP), with the potential for prospective adaptation to current good manufacturing practice (cGMP) toward clinical compliance.
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A human-derived 3D brain organoid model to study JC virus infection.
Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination which lead to neurological dysfunction. The pathogenesis of PML is poorly understood due to the lack of in vitro or animal models to study mechanisms of disease as the virus most efficiently infects only human cells. We developed a human-derived brain organotypic system (also called brain organoid) to model JCV infection. The model was developed by using human-induced pluripotent stem cells (iPSC) and culturing them in 3D to generate an organotypic model containing neurons, astrocytes, and oligodendrocytes which recapitulates aspects of the environment of the human brain. We infected the brain organoids with the JCV MAD4 strain or cerebrospinal fluid of a patient with PML. The organoids were assessed for evidence of infection by qPCR, immunofluorescence, and electron microscopy at 1, 2, and 3 weeks post-exposure. JCV infection in both JCV MAD4 strain and PML CSF-exposed brain organoids was confirmed by immunocytochemical studies demonstrating viral antigens and electron microscopy showing virion particles in the nuclear compartment of oligodendrocytes and astrocytes. No evidence of neuronal infection was visualized. Infection was also demonstrated by JCV qPCR in the virus-exposed organoids and their media. In conclusion, the brain organoid model of JCV infection establishes a human model suitable for studying the mechanisms of JCV infection and pathogenesis of PML and may facilitate the exploration of therapeutic approaches.
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Zooming into finer brain structures in vitro.
Regionalized organoids have recently been developed to resemble a particular brain region. However, generating organoids with even finer sub-regional resolution has proven challenging. In this issue of Cell Stem Cell, Kiral et al.1 report a new organoid model resembling the human ventral thalamus and thalamic reticular nucleus.