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Cerebral organoids: emerging ex vivo humanoid models of glioblastoma.
Glioblastoma is an aggressive form of brain cancer that has seen only marginal improvements in its bleak survival outlook of 12-15 months over the last forty years. There is therefore an urgent need for the development of advanced drug screening platforms and systems that can better recapitulate glioblastoma's infiltrative biology, a process largely responsible for its relentless propensity for recurrence and progression. Recent advances in stem cell biology have allowed the generation of artificial tridimensional brain-like tissue termed cerebral organoids. In addition to their potential to model brain development, these reagents are providing much needed synthetic humanoid scaffolds to model glioblastoma's infiltrative capacity in a faithful and scalable manner. Here, we highlight and review the early breakthroughs in this growing field and discuss its potential future role for glioblastoma research.
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Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling.
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant global health issue. This novel virus's high morbidity and mortality rates have prompted the scientific community to quickly find the best COVID-19 model to investigate all pathological processes underlining its activity and, more importantly, search for optimal drug therapy with minimal toxicity risk. The gold standard in disease modeling involves animal and monolayer culture models; however, these models do not fully reflect the response to human tissues affected by the virus. However, more physiological 3D in vitro culture models, such as spheroids and organoids derived from induced pluripotent stem cells (iPSCs), could serve as promising alternatives. Different iPSC-derived organoids, such as lung, cardiac, brain, intestinal, kidney, liver, nasal, retinal, skin, and pancreatic organoids, have already shown immense potential in COVID-19 modeling. In the present comprehensive review article, we summarize the current knowledge on COVID-19 modeling and drug screening using selected iPSC-derived 3D culture models, including lung, brain, intestinal, cardiac, blood vessels, liver, kidney, and inner ear organoids. Undoubtedly, according to reviewed studies, organoids are the state-of-the-art approach to COVID-19 modeling.
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The current approaches to modeling the brain ischemia-reperfusion and inflammation: from animal models toward vascularized and neuroimmune cerebral organoids.
For several decades, the modeling of brain diseases in experimental animals has remained one of the key components of studying the pathogenesis of central nervous system pathology and searching for new methods of prevention and therapy. In recent years, new approaches to modeling pathological conditions in vitro have been in active development; these approaches will not only reduce the number of animal studies but also allow us to take a step toward reproducing the human-specific mechanisms of brain pathology. In this review, we characterize the most common rodent models of cerebral ischemia and reperfusion, as well as neuroinflammation inherent to neurodegeneration (in particular, Parkinson's disease), which are reproduced in vivo. This review addresses engineering and technical challenges and the prospects for the development of brain pathology models in vitro, e.g., vascularized and microglia-containing/neuroimmune cerebral organoids, which may be useful in overcoming the shortcomings and limitations of the current in vivo models.
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Differential synaptic signaling responses in human cortical organoids after photon and proton irradiation.
Brain tumors are the most common solid cancer in children, with radiotherapy being a primary treatment. Proton therapy, with its precise dose distribution, is increasingly being used in these patients to minimize damage to the developing brain. However, the biological effects of proton irradiation on the human brain remain unclear. To investigate this, human cortical organoids were exposed to conventional photons, plateau protons, and spread-out Bragg peak (SOBP) protons, followed by comparative transcriptomic profiling. While photons and protons induced similar transcriptional profiles characterized by apoptosis and downregulation of DNA replication, SOBP protons uniquely downregulated genes involved in brain development and synaptic signaling. Functional calcium imaging, cell deconvolution analysis, and immunostaining indicated that SOBP protons impaired neural network function, due to reduced synaptic density and loss in excitatory neuron progenitors. These findings underscore the distinct biological effects of SOBP protons and their potential impact on the developing brain.
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Autism in Three Dimensions: Using Brain Organoids to Study Potential Gene-Environment Interactions.
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Human brain organoids influence rat behaviour.
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From Cells to Selves and Back: Human Neurodiversity at Single-Cell Resolution.
Human brain development is characterized by a complex cellular and molecular landscape, which varies both within and between individuals. Here, we explore the transformative impact of single-cell omics technologies on our understanding of human neurodiversity and neurocomplexity. We trace historical progressions of cellular and molecular biology, highlighting the cell as a pivotal "place holder" for biological inquiry, as a basis to better understand the current revolution of single-cell profiling, enabling the study of individual genomes and environmental interactions at unprecedented resolution. Starting from the challenges of defining cell types and states within neurodevelopment, we emphasize the significance of moving beyond categorical distinctions to understand the molecular basis of interindividual neurodiversity, including genetics, environment, and developmental stochasticity. We introduce the concept of "in vitro epidemiology," leveraging neural organoids and multiplexing approaches to model population-scale cohorts in vitro and thus enabling the dissection of gene-environment interactions at single-cell resolution. We further discuss technical advancements and computational methodologies that are driving the field forward, including the efforts to create comprehensive cell atlases of the human brain and the emerging challenges in data integration and analysis. Finally, we anticipate future perspectives for single-cell studies and neural organoids in advancing our understanding of neurobiology and cell-based strategies for drug discovery and personalized treatment.
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Engineered Human Induced Pluripotent Cells Enable Genetic Code Expansion in Brain Organoids.
Human induced pluripotent stem cell (hiPSC) technology has revolutionized studies on human biology. A wide range of cell types and tissue models can be derived from hiPSCs to study complex human diseases. Here, we use PiggyBac-mediated transgenesis to engineer hiPSCs with an expanded genetic code. We demonstrate that genomic integration of expression cassettes for a pyrrolysyl-tRNA synthetase (PylRS), pyrrolysyl-tRNA (PylT) and the target protein of interest enables site-specific incorporation of a non-canonical amino acid (ncAA) in response to an amber stop codon. Neural stem cells, neurons and brain organoids derived from the engineered hiPSCs continue to express the amber suppression machinery and produce ncAA-bearing reporter. The incorporated ncAA can serve as a minimal bioorthogonal handle for further modifications by labeling with fluorescent dyes. Site-directed ncAA mutagenesis will open a wide range of applications to probe and manipulate proteins in brain organoids and other hiPSC-derived cell types and complex tissue models.
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Engineering Mesenchymal Stem Cell Spheroids and Brain Organoids: Advanced 3D Culture Platforms for Neurodegenerative Disease Cell Therapy.
Cell therapy for neurodegenerative diseases (NDs) is considered a promising strategy to halt disease progression. Currently, most clinically applied cells are derived from two-dimensional (2D) cultures. However, 2D-cultured mesenchymal stem cells (MSCs) are prone to aging and functional deterioration after multiple passages, and the availability of neural precursor cells for cell replacement therapy remains limited. In contrast, three-dimensional (3D) cell cultures have garnered significant attention due to their unique 3D spatial interactions. The unique spatial architecture of 3D culture not only enhances cell-cell and cell-extracellular matrix (ECM) interactions in MSC spheroids, thereby preserving MSCs properties, but also facilitates developmental processes of brain organoids derived from pluripotent stem cells, including embryogenesis, morphogenesis, and organogenesis. This review highlights the therapeutic ability of 3D-cultured MSC spheroids and brain organoids for NDs and summarizes advanced engineering platforms for their production. Future research should integrate the strengths of both technologies by establishing standardized quality control systems and scalable production processes to harness the microenvironmental modulation capacity of MSC spheroids and the precise cell replacement ability of brain organoids, ultimately advancing personalized therapies for NDs.
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Electroporation of Sliced Human Cortical Organoids for Studies of Gene Function.
Human cortical organoids have become important tools for studying human brain development, neurodevelopmental disorders, and human brain evolution. Studies analyzing gene function by overexpression or knockout have been instrumental in animal models to provide mechanistic insights into the regulation of neocortex development. Here, we present a detailed protocol for CRISPR/Cas9-mediated acute gene knockout by electroporation of sliced human cortical organoids. The slicing of cortical organoids aids the identification of ventricle-like structures for injection and subsequent electroporation, making this a particularly well-suited model for acute genetic manipulation during human cortical development. We describe the design of guide RNAs and the validation of targeting efficiency in vitro and in cortical organoids. Electroporation of cortical organoids is performed at mid-neurogenic stages, enabling the targeting of most major cell classes in the developing neocortex, including apical radial glia, basal progenitor cells, and neurons. Taken together, the electroporation of sliced human cortical organoids represents a powerful technique to investigate gene function, gene regulation, and cell morphology during cortical development.