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Generation of ventralized human thalamic organoids with thalamic reticular nucleus.
Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain.
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The uses of 3D human brain organoids for neurotoxicity evaluations: A review.
Neurotoxicity studies aim at understanding the toxic effects and mechanisms of toxicants to human central nervous systems (CNS). However, human brains are the most complex organs, whereas the most commonly used models, such as 2D cell cultures and animal brains, are probably too simple to predict the responses of human brains. Embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)-based 3D human brain organoids hold unprecedented promise for the understanding of neurodevelopment and brain disease development. This review summarizes recent advances of using 3D human brain organoids for neurotoxicity studies. Comparative studies showed that 3D human brain organoids could support the findings obtained by animal or cohort studies, indicating that 3D human brain organoids are reliable models to evaluate the developmental neurotoxicity. 3D human brain organoids have been used to understand the toxicological mechanisms by using both conventional toxicological methods to investigate the signaling pathway changes as well as single cell RNA-sequencing to understand the neuron diversity. Some studies also used brain organoids carrying gene mutations or with virus infections to understand the toxicological responses of brains under diseased conditions. Although there are still limitations associated, 3D human brain organoids are promising tools for future neurotoxicity studies.
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Modeling Glioblastoma with Brain Organoids: New Frontiers in Oncology and Space Research.
Glioblastoma (GBM) is the most malignant primary brain tumor, characterized by extensive heterogeneity, invasiveness, infiltrating behavior, and resistance to standard therapies, including radiation and temozolomide (TMZ). Despite considerable efforts in investigating its pathophysiology, GBM represents one of the most challenging cancers to treat, with a median survival rate under 15 months and a 5-year survival rate below 5%. A major barrier to progress in GBM therapy development is the lack of reliable preclinical models that faithfully recapitulate the tumor's molecular heterogeneity, invasive behavior, and complex microenvironment. Traditional cell lines and xenograft models often fail to reflect the key pathological features of human GBM, including immune suppression, vascular abnormalities, and treatment resistance. In recent years, attention has focused on the development of numerous clinically relevant GBM models based on brain organoids as a powerful "disease-in-a-dish" model. They strongly mimic GBM key histopathological and molecular features, such as the tumor's cellular heterogeneity, genetic landscape, and microenvironment, enabling more accurate studies of tumor biology, invasion, and therapeutic response in a controlled in vitro setting. Notably, research in microgravity offers a unique and promising platform to study cancer biology under conditions that enhance tissue self-organization, mimic aspects of tumor growth, and potentially unveil novel therapeutic vulnerabilities. This review compares organoids to conventional preclinical models, tracing their historical development and salient features, focusing on the preparation and use of organoids in GBM research. We also introduce a novel and promising field of organoid application: space-based organoid brain research.
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An integrated transcriptomic cell atlas of human neural organoids.
Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the human brain are covered by existing protocols, and it has been difficult to quantitatively assess organoid variation and fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated human neural organoid cell atlas totalling more than 1.7 million cells1-26. Mapping to developing human brain references27-30 shows primary cell types and states that have been generated in vitro, and estimates transcriptomic similarity between primary and organoid counterparts across protocols. We provide a programmatic interface to browse the atlas and query new datasets, and showcase the power of the atlas to annotate organoid cell types and evaluate new organoid protocols. Finally, we show that the atlas can be used as a diverse control cohort to annotate and compare organoid models of neural disease, identifying genes and pathways that may underlie pathological mechanisms with the neural models. The human neural organoid cell atlas will be useful to assess organoid fidelity, characterize perturbed and diseased states and facilitate protocol development.
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Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex.
Realizing the full utility of brain organoids to study human development requires understanding whether organoids precisely replicate endogenous cellular and molecular events, particularly since acquisition of cell identity in organoids can be impaired by abnormal metabolic states. We present a comprehensive single-cell transcriptomic, epigenetic, and spatial atlas of human cortical organoid development, comprising over 610,000 cells, from generation of neural progenitors through production of differentiated neuronal and glial subtypes. We show that processes of cellular diversification correlate closely to endogenous ones, irrespective of metabolic state, empowering the use of this atlas to study human fate specification. We define longitudinal molecular trajectories of cortical cell types during organoid development, identify genes with predicted human-specific roles in lineage establishment, and uncover early transcriptional diversity of human callosal neurons. The findings validate this comprehensive atlas of human corticogenesis in vitro as a resource to prime investigation into the mechanisms of human cortical development.
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Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.
Human brain organoids represent a remarkable platform for modelling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses revealed that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays revealed that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.
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Brain Organoids: Expanding Our Understanding of Human Development and Disease.
Stem cell-derived brain organoids replicate important stages of the prenatal human brain development and combined with the induced pluripotent stem cell (iPSC) technology offer an unprecedented model for investigating human neurological diseases including autism and microcephaly. We describe the history and birth of organoids and their application, focusing on cerebral organoids derived from embryonic stem cells and iPSCs. We discuss new insights into organoid-based model of schizophrenia and shed light on challenges and future applications of organoid-based disease model system. This review also suggests hitherto unrevealed potential applications of organoids in combining with new technologies such as nanophotonics/optogenomics for controlling brain development and atomic force microscopy for studying mechanical forces that shape the developing brain.
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Toward the formation of neural circuits in human brain organoids.
Because of the ability to recapitulate normal developmental processes, brain organoids derived from pluripotent stem cells are an important experimental resource to investigate the development and pathogenesis of human brains. Although brain organoids are used in research on diseases such as microcephaly, it has traditionally been difficult to analyze diseases that affect neuronal networks between distant brain regions, as effective brain organoids containing multiple brain regions with defined connectivity have yet to be established. In this review, we discuss strategies to construct such organoids and provide a review on recent progress on brain organoids.
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Studying Human Neurodevelopment and Diseases Using 3D Brain Organoids.
In vitro differentiation of pluripotent stem cells provides a systematic platform to study development and disease. Recent advances in brain organoid technology have created new opportunities to investigate the formation and function of the human brain, under physiological and pathological conditions. Brain organoids can be generated to model the cellular and structural development of the human brain, and allow the investigation of the intricate interactions between resident neural and glial cell types. Combined with new advances in gene editing, imaging, and genomic analysis, brain organoid technology can be applied to address questions pertinent to human brain development, disease, and evolution. However, the current iterations of brain organoids also have limitations in faithfully recapitulating the in vivo processes. In this perspective, we evaluate the recent progress in brain organoid technology, and discuss the experimental considerations for its utilization.Dual Perspectives Companion Paper: Integrating CRISPR Engineering and hiPSC-Derived 2D Disease Modeling Systems, by Kristina Rehbach, Michael B. Fernando, and Kristen J. Brennand.
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Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development.
Human organoids are small, self-organized, three-dimensional (3D) tissue cultures that have started to revolutionize medical science in terms of understanding disease, testing pharmacologically active compounds, and offering novel ways to treat disease. Organoids of the liver, kidney, intestine, lung, and brain have been developed in recent years. Human brain organoids are used for understanding pathogenesis and investigating therapeutic options for neurodevelopmental, neuropsychiatric, neurodegenerative, and neurological disorders. Theoretically, several brain disorders can be modeled with the aid of human brain organoids, and hence the potential exists for understanding migraine pathogenesis and its treatment with the aid of brain organoids. Migraine is considered a brain disorder with neurological and non-neurological abnormalities and symptoms. Both genetic and environmental factors play essential roles in migraine pathogenesis and its clinical manifestations. Several types of migraines are classified, for example, migraines with and without aura, and human brain organoids can be developed from patients with these types of migraines to study genetic factors (e.g., channelopathy in calcium channels) and environmental stressors (e.g., chemical and mechanical). In these models, drug candidates for therapeutic purposes can also be tested. Here, the potential and limitations of human brain organoids for studying migraine pathogenesis and its treatment are communicated to generate motivation and stimulate curiosity for further research. This must, however, be considered alongside the complexity of the concept of brain organoids and the neuroethical aspects of the topic. Interested researchers are invited to join the network for protocol development and testing the hypothesis presented here.