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Neurotropic Effects of SARS-CoV-2 Modeled by the Human Brain Organoids.
COVID-19, caused by SARS-CoV-2, is a socioeconomic burden, which exhibits respiratory illness along with unexpected neurological complications. Concerns have been raised about whether the observed neurological symptoms are due to direct effects on CNS or associated with the virus's systemic effect. Recent SARS-CoV-2 infection studies using human brain organoids revealed that SARS-CoV-2 targets human neurons. Human brain organoids are stem cell-derived reductionist experimental systems that have highlighted the neurotropic effects of SARS-CoV-2. Here, we summarize the neurotoxic effects of SARS-CoV-2 using brain organoids and comprehensively discuss how brain organoids could further improve our understanding when they are fine-tuned.
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Cerebral organoids and their potential for studies of brain diseases in domestic animals.
The brain is a complex organ and any model for studying it in its normal and pathological aspects becomes a tool of choice for neuroscientists. The mastering and dissemination of protocols allowing brain organoids development have paved the way for a whole range of new studies in the field of brain development, modeling of neurodegenerative or neurodevelopmental diseases, understanding tumors as well as infectious diseases that affect the brain. While studies are so far limited to the use of human cerebral organoids, there is a growing interest in having similar models in other species. This review presents what is currently developed in this field, with a particular focus on the potential of cerebral organoids for studying neuro-infectious diseases in human and domestic animals.
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COVID-19 lessons from the dish: Dissecting CNS manifestations through brain organoids.
COVID-19 is increasingly understood as a systemic disease with pathogenic manifestations beyond the respiratory tract. Recent work by Ramani et al (2020) dissects the cellular and molecular mechanisms of SARS-CoV-2's neurotrophic properties, using viral exposure of human brain organoids. Their findings highlight neurons as primary target of cerebral SARS-CoV-2 infection and uncover its Tau-related neurotoxicity.
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A tabletop blast device for the study of the long-term consequences of traumatic brain injury on brain organoids.
Traumatic brain injury (TBI) is the leading environmental risk factor for neurodegenerative diseases, yet its molecular link to chronic neurodegeneration is unclear. While animal models of TBI are commonly used, emerging research suggests that induced pluripotent stem cell (iPSC)-derived brain organoids offer a promising human-specific alternative, particularly for studying processes like cryptic exon splicing. However, widespread use has been limited by methodological variability and the need for expensive and specialized equipment. To address these challenges, we developed a tabletop blast device capable of delivering highly reproducible pressure waves via a gravity-based pressure chamber. We validated the applicability of our approach by assessing the short- and long-term consequences of mechanical stress on brain organoids after pressure wave exposure. Our approach provides a controllable and reproducible method to apply complex pressure cycles on brain organoids, enabling broader accessibility for studying the mechanistic links between TBI and neurodegeneration in a human-relevant context.
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Zika must remain a high priority.
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Trends and challenges in modeling glioma using 3D human brain organoids.
The human brain organoids derived from pluripotent cells are a new class of three-dimensional tissue systems that recapitulates several neural epithelial aspects. Brain organoids have already helped efficient modeling of crucial elements of brain development and disorders. Brain organoids' suitability in modeling glioma has started to emerge, offering another usefulness of brain organoids in disease modeling. Although the current state-of-the organoids mostly reflect the immature state of the brain, with their vast cell diversity, human brain-like cytoarchitecture, feasibility in culturing, handling, imaging, and tractability can offer enormous potential in reflecting the glioma invasion, integration, and interaction with different neuronal cell types. Here, we summarize the current trend of employing brain organoids in glioma modeling and discuss the immediate challenges. Solving them might lay a foundation for using brain organoids as a pre-clinical 3D substrate to dissect the glioma invasion mechanisms in detail.
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PAUPAR and PAX6 sequentially regulate human embryonic stem cell cortical differentiation.
Long noncoding RNAs (lncRNAs) play a wide range of roles in the epigenetic regulation of crucial biological processes, but the functions of lncRNAs in cortical development are poorly understood. Using human embryonic stem cell (hESC)-based 2D neural differentiation approach and 3D cerebral organoid system, we identified that the lncRNA PAUPAR, which is adjacent to PAX6, plays essential roles in cortical differentiation by interacting with PAX6 to regulate the expression of a large number of neural genes. Mechanistic studies showed that PAUPAR confers PAX6 proper binding sites on the target neural genes by directly binding the genomic regions of these genes. Moreover, PAX6 recruits the histone methyltransferase NSD1 through its C-terminal PST enrichment domain, then regulate H3K36 methylation and the expression of target genes. Collectively, our data reveal that the PAUPAR/PAX6/NSD1 complex plays a critical role in the epigenetic regulation of hESC cortical differentiation and highlight the importance of PAUPAR as an intrinsic regulator of cortical differentiation.
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Standardizing a method for functional assessment of neural networks in brain organoids.
During the last decade brain organoids have emerged as an attractive model system, allowing stem cells to be differentiated into complex 3D models, recapitulating many aspects of human brain development. Whilst many studies have analysed anatomical and cytoarchitectural characteristics of organoids, their functional characterisation has been limited, and highly variable between studies. Standardised, consistent methods for recording functional activity are critical to providing a functional understanding of neuronal networks at the synaptic and network level that can yield useful information about functional network phenotypes in disease and healthy states. In this study we outline a detailed methodology for calcium imaging and Multi-Electrode Array (MEA) recordings in brain organoids. To illustrate the utility of these functional interrogation techniques in uncovering induced differences in neural network activity we applied various stimulating media protocols. We demonstrate overlapping information from the two modalities, with comparable numbers of active cells in the four treatment groups and an increase in synchronous behaviour in BrainPhys treated groups. Further development of analysis pipelines to reveal network level changes in brain organoids will enrich our understanding of network formation and perturbation in these structures, and aid in the future development of drugs that target neurological disorders at the network level.
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Exploring aging interventions in human brain organoids.
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Generation of glioblastoma patient-derived organoids and mouse brain orthotopic xenografts for drug screening.
Robust patient-derived platforms that recapitulate the cellular and molecular fingerprints of glioblastoma are crucial for developing effective therapies. Here, we describe a chemically defined protocol for 3D culture and propagation of glioblastoma in 3D gliospheres, patient-derived organoids (PDOs), mouse brain orthotopic xenografts (PDOXs), and downstream drug and immunofluorescence assays. This simple-to-follow protocol allows assessing drug sensitivity, on-target activity, and combined drug synergy. Promising therapies can then be validated in PDOXs for translation in precision medicine oncology trials. For complete details on the use and execution of this protocol, please refer to Chadwick et al. (2020) and Patrizii et al. (2018).