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Building Immunocompetent Cerebral Organoids From a Developmental Perspective.
Cerebral organoids derived from human induced pluripotent stem cells (iPSCs) are increasingly becoming essential tools to study the human brain, from understanding pathological mechanisms in neurodevelopmental, neurodegenerative, and infectious diseases to identifying genetic risks and biomarkers. To resemble the brain environment, cerebral organoids must contain microglia, the resident macrophages of the brain parenchyma that are essential for its homeostasis. As microglia derive from the yolk sac, they are not present in conventional brain organoids, which are generated by reprogramming iPSCs towards the neuroectodermal lineage and must be exogenously incorporated through a variety of strategies. Once in the organoid parenchyma, microglia must recapitulate their developmental milestones to achieve full immunocompetence, reaching a mature transcriptional profile and morphology, a tessellated distribution, efficient phagocytosis, and controlled inflammatory responses. In this review, we will summarize recent protocols that have been developed to generate human microglial-containing cerebral organoids (MCCOs), focusing on the methods used to assess the level of microglial maturation compared to their in vivo counterparts. We provide a series of recommendations to assess microglial immunocompetence using stringent quantitative approaches that will promote developing standardized protocols to culture MCCOs.
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Brain organoid maturation and implantation integration based on electrical signals input.
INTRODUCTION: Brain organoids are believed to be able to regenerate impaired neural circuits and reinstate brain functionality. The neuronal activity of organoids is considered a crucial factor for restoring host function after implantation. However, the optimal stage of brain organoid post-transplantation has not yet been established. External electrical signal plays a crucial role in the physiology and development of a majority of human tissues. However, whether electrical input modulates the development of brain organoids, making them ideal transplant donors, is elusive. METHODS: Bioelectricity was input into cortical organoids by electrical stimulation (ES) with a multi-electrode array (MEA) to obtain a better-transplanted candidate with better viability and maturity, realizing structural-functional integration with the host brain. RESULTS: We found that electrical stimulation facilitated the differentiation and maturation of organoids, displaying well-defined cortical plates and robust functional electrophysiology, which was probably mediated via the pathway of calcium-calmodulin (CaM) dependent protein kinase II (CAMK II)-protein kinase A (PKA)-cyclic-AMP response binding protein (pCREB). The ES-pretreated D40 organoids displayed superior cell viability and higher cell maturity, and were selected to transplant into the damaged primary sensory cortex (S1) of host. The enhanced maturation was exhibited within grafts after transplantation, including synapses and complex functional activities. Moreover, structural-functional integration between grafts and host was observed, conducive to strengthening functional connectivity and restoring the function of the host injury. CONCLUSION: Our findings supported that electrical stimulation could promote the development of cortical organoids. ES-pretreated organoids were better-transplanted donors for strengthening connectivity between grafts and host. Our work presented a new physical approach to regulating organoids, potentially providing a novel translational strategy for functional recovery after brain injury. In the future, the development of 3D flexible electrodes is anticipated to overcome the drawbacks of 2D planar MEA, promisingly achieving multimodal stimulation and long-term recordings of brain organoids.
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Human Brain Organoid-Enabling Discoveries Reach the Clinic: A Translational Inflection Point.
Human brain organoids have evolved from early neurodevelopmental models into platforms for therapeutic discovery. Here, we highlight two cases in which organoid-derived findings enabled FDA-approved clinical trials. Patient-derived organoids modeling Pitt-Hopkins syndrome revealed human-specific, TCF4-dependent abnormalities and supported the development of a regulated AAV gene therapy. In parallel, Rett syndrome organoids cultured aboard the International Space Station uncovered space-induced neural senescence, characterized by retroelement-associated neuroinflammation, prompting evaluation of antiretroviral therapy. These examples illustrate how organoids can reveal disease mechanisms that are inaccessible or incompletely reproduced in animal models, while animal studies remain essential for validation and safety assessment. As the field advances, matching model complexity to experimental purpose-and ensuring reproducibility, scalability, and accessibility-will be critical. Human brain organoids are crossing a translational threshold, emerging as engines of therapeutic discovery and gateways to clinical intervention.
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Mouse vs man: Organoid models of brain development & disease.
Brain organoids have rapidly become established as promising tools for studying both the normal embryonic development of the brain and the mechanistic roots of neurodevelopmental disorders. Most recent studies are based on brain organoids derived from human pluripotent stem cells (PSCs), as these are likely to be the best way to understand normal human development and disease. However, brain organoids grown from mouse cells still have a role to play. We discuss recent work showing how mice and mouse organoids can be employed to complement studies using human organoids. Mouse stem cell-derived organoids are useful for the development of improved protocols to generate organoids, including brain region-specific organoids. Importantly, the wealth of existing in vivo data on mouse brain development together with detailed descriptions of mutant phenotypes provide invaluable points of comparison to validate organoids as tools to study the genetics of brain development. Further, organoids have significant potential to replace or reduce the numbers of animals used in studies of normal brain development.
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Engineering Stem Cell Organoids.
Organoid systems leverage the self-organizing properties of stem cells to create diverse multi-cellular tissue proxies. Most organoid models only represent single or partial components of a tissue, and it is often difficult to control the cell type, organization, and cell-cell/cell-matrix interactions within these systems. Herein, we discuss basic approaches to generate stem cell-based organoids, their advantages and limitations, and how bioengineering strategies can be used to steer the cell composition and their 3D organization within organoids to further enhance their utility in research and therapies.
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Generation and Fusion of Human Cortical and Medial Ganglionic Eminence Brain Organoids.
Three-dimensional (3D) brain organoid culture has become an essential tool for investigating human brain development and modeling neurological disorders during the past few years. Given the specific regionalization during brain development, it is important to produce distinct brain organoids that reproduce different brain regions and their interaction. The authors' laboratory recently established the platform to generate brain organoids resembling the medial ganglionic eminence (MGE), a specific brain region responsible for interneurogenesis, and found when fusing with organoid resembling the cortex, the fused organoids enabled modeling of interneuron migration in the brain. This unit describes four basic protocols that have been successfully applied in the authors' laboratory, covering the generation of embryonic body (EB) with neuroectodermal fate, the production of MGE organoids (hMGEOs) and cortical organoids (hCOs), and the fusion of the two organoids.
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Lab-grown mini-brains upgraded.
Three-dimensional brain organoid models have come into the spotlight as in vitro tools to recapitulate complex features of the brain. Four recent papers now leverage current technologies to generate new flavours of brain organoids and address aspects of brain biology which, to date, have been challenging to explore.
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Recent Advances in Brain Organoid Technology for Human Brain Research.
Brain organoids are self-assembled three-dimensional aggregates with brain-like cell types and structures and have emerged as new model systems that can be used to investigate human neurodevelopment and neurological disorders. However, brain organoids are not as mature and functional as real human brains due to limitations of the culture system with insufficient developmental patterning signals and a lack of components that are important for brain development and function, such as the non-neural population and vasculature. In addition, establishing the desired brain-like environment and monitoring the complex neural networks and physiological functions of the brain organoids remain challenging. The current protocols to generate brain organoids also have problems with heterogeneity and batch variation due to spontaneous self-organization of brain organoids into complex architectures of the brain. To address these limitations of current brain organoid technologies, various engineering platforms, such as extracellular matrices, fluidic devices, three-dimensional bioprinting, bioreactors, polymeric scaffolds, microelectrodes, and biochemical sensors, have been employed to improve neuronal development and maturation, reduce structural heterogeneity, and facilitate functional analysis and monitoring. In this review, we provide an overview of the latest engineering techniques that overcome these limitations in the production and application of brain organoids.
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Building brains: using brain organoids to study neural development and disease.
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Optogenetics in the Era of Cerebral Organoids.
The human brain has been deemed the most complex organ and has captivated neuroscientists for decades. Most studies of this organ have relied on reductionist model systems. Although all model systems are essentially wrong, cerebral organoids so far represent the closest recapitulation of human brain development and disease both in terms of cell diversity and organization. The optogenetic technique can be used in this context to study the functional neuroanatomy of the brain, to examine the neural circuits, and to determine the etiology of neurological disorders. In this opinion article, we suggest ways in which optogenetics can be combined with cerebral organoids to allow unprecedented precision and accuracy in studying normal and aberrant neurodevelopmental processes and, as well, neurodegenerative diseases.