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Host-virus determinants of Ebola virus persistence in a human cerebral organoid model.
Ebola virus (EBOV) causes Ebola virus disease (EVD), a multisystemic human disease associated with an extraordinarily high case-fatality rate. EVD survivors may experience recrudescent inflammation with viral persistence in immune-privileged tissues, including the central nervous system (CNS). Persistence, defined by ongoing replication of the EBOV genome beyond the acute disease phase, may lead to virion production. Productive persistence has been linked to re-initiation of EVD outbreaks. We developed a human cerebral organoid model to investigate the host and viral determinants of EBOV CNS persistence. In this model, EBOV persistence for 120 days was sustained by continuous infection of astrocytes and neurons and the recruitment and infection of microglia. This was accompanied by the emergence of EBOV defective viral genomes and genomic subvariants, cell-to-cell transmission, activation of cell-specific innate immunity, and late brain organoid inflammation, indicating that persistent infection of EBOV within immune-privileged niches drives local inflammation.
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The sixth sense of the brain: interoception in organoid study.
Interoception is the process by which the nervous system senses, integrates, and interprets signals arising from within the body, thereby enabling the brain to monitor and regulate physiological functions. Often described as a "sixth sense", interoception links internal physiological states to brain-mediated homeostatic control, whereas sight, smell, hearing, taste, and touch primarily convey information from the external environment. Organoids are three-dimensional tissue models derived from stem or progenitor cells that reproduce selected structural and functional features of native organs. Because organoids are increasingly used in disease modeling, drug testing, and regenerative research, their integration with neural, endocrine, immune, and vascular components offers an opportunity to investigate brain-body communication. Conversely, organoid-based systems may provide experimentally tractable models for interoception. This review defines interoception and organoid technologies, examines brain-centered communication with skeletal and intestinal systems, and discusses how brain, bone, and intestinal organoids and assembloids could advance interoception research. In particular, organoid-based models may enable mechanistic investigation of neuroendocrine pathways, including the hypothalamic-pituitary-adrenal (HPA) axis, and thereby provide new insights into physiological regulation and disease progression.
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Review of Artificial Intelligence Applications and Algorithms for Brain Organoid Research.
The human brain organoid is a miniature three-dimensional tissue culture that can simulate the structure and function of the brain in an in vitro culture environment. Although we consider that human brain organoids could be used to understand brain development and diseases, experimental models of human brain organoids are so highly variable that we apply artificial intelligence (AI) techniques to investigate the development mechanism of the human brain. Therefore, this study briefly reviewed commonly used AI applications for human brain organoid-magnetic resonance imaging, electroencephalography, and gene editing techniques, as well as related AI algorithms. Finally, we discussed the limitations, challenges, and future study direction of AI-based technology for human brain organoids.
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Transforming Brain Organoids Into Functional Platforms: Convergence of Engineering, Imaging, AI, and Ethics.
Brain organoids are self-organizing 3D aggregates derived from pluripotent stem cells and thus mirror many aspects of human brain development, including gene expression programs, spatial organization, and neuron subtype specification. As a result, these organoids have been used to emulate neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Yet, their maturation remains fundamentally constrained by diffusion-limited necrosis, incomplete vascularization, limited visualization, and the absence of large-scale circuit integration, which collectively prevent progression beyond the fetal stage. These intrinsic limitations have catalyzed a convergence across microfluidics, biofabrication, imaging, and ethical frameworks, giving rise to a multidisciplinary movement aimed at enhancing organoid viability, reproducibility, and physiological relevance. This perspective examines how these technologies are transforming brain organoids from developmental models into experimentally robust, functional platforms.
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Engineering the Physical Microenvironment into Neural Organoids for Neurogenesis and Neurodevelopment.
Understanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell-derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting-edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid-based research and neuroscience.
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Brain organoid formation on decellularized porcine brain ECM hydrogels.
Human brain tissue models such as cerebral organoids are essential tools for developmental and biomedical research. Current methods to generate cerebral organoids often utilize Matrigel as an external scaffold to provide structure and biologically relevant signals. Matrigel however is a nonspecific hydrogel of mouse tumor origin and does not represent the complexity of the brain protein environment. In this study, we investigated the application of a decellularized adult porcine brain extracellular matrix (B-ECM) which could be processed into a hydrogel (B-ECM hydrogel) to be used as a scaffold for human embryonic stem cell (hESC)-derived brain organoids. We decellularized pig brains with a novel detergent- and enzyme-based method and analyzed the biomaterial properties, including protein composition and content, DNA content, mechanical characteristics, surface structure, and antigen presence. Then, we compared the growth of human brain organoid models with the B-ECM hydrogel or Matrigel controls in vitro. We found that the native brain source material was successfully decellularized with little remaining DNA content, while Mass Spectrometry (MS) showed the loss of several brain-specific proteins, while mainly different collagen types remained in the B-ECM. Rheological results revealed stable hydrogel formation, starting from B-ECM hydrogel concentrations of 5 mg/mL. hESCs cultured in B-ECM hydrogels showed gene expression and differentiation outcomes similar to those grown in Matrigel. These results indicate that B-ECM hydrogels can be used as an alternative scaffold for human cerebral organoid formation, and may be further optimized for improved organoid growth by further improving protein retention other than collagen after decellularization.
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Understanding Immune-Driven Brain Aging by Human Brain Organoid Microphysiological Analysis Platform.
The aging of the immune system drives systemic aging and the pathogenesis of age-related diseases. However, a significant knowledge gap remains in understanding immune-driven aging, especially in brain aging, due to the limited current in vitro models of neuroimmune interaction. Here, the authors report the development of a human brain organoid microphysiological analysis platform (MAP) to discover the dynamic process of immune-driven brain aging. The organoid MAP is created by 3D printing that confines organoid growth and facilitates cell and nutrition perfusion, promoting organoid maturation and their committment to forebrain identity. Dynamic rocking flow is incorporated into the platform that allows to perfuse primary monocytes from young (20 to 30-year-old) and aged (>60-year-old) donors and culture human cortical organoids to model neuroimmune interaction. The authors find that the aged monocytes increase infiltration and promote the expression of aging-related markers (e.g., higher expression of p16) within the human cortical organoids, indicating that aged monocytes may drive brain aging. The authors believe that the organoid MAP may provide promising solutions for basic research and translational applications in aging, neural immunological diseases, autoimmune disorders, and cancer.
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Mapping the Ethical Issues of Brain Organoid Research and Application.
In 2008, researchers created human three-dimensional neural tissue - known as the pioneering work of "brain organoids." In recent years, some researchers have transplanted human brain organoids into animal brains for applicational purposes. With these experiments have come many ethical concerns. It is thus an urgent task to clarify what is ethically permissible and impermissible in brain organoid research. This paper seeks (1) to sort out the ethical issues related to brain organoid research and application and (2) to propose future directions for additional ethical consideration and policy debates in the field. Toward (1), this paper first outlines the current state of brain organoid research, and then briefly responds to previously raised related ethical concerns. Looking next at anticipated scientific developments in brain organoid research, we will discuss (i) ethical issues related to in vitro brain organoids, (ii) ethical issues raised when brain organoids form complexes or have relationships with other entities, and (iii) ethical issues of research ethics and governance. Finally, in pursuit of (2), we propose research policies that are mindful of the ethics of brain organoid research and application and also suggest the need for an international framework for research and application of brain organoids.
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Brain organoid: a 3D technology for investigating cellular composition and interactions in human neurological development and disease models in vitro.
The study of human brain physiology, including cellular interactions in normal and disease conditions, has been a challenge due to its complexity and unavailability. Induced pluripotent stem cell (iPSC) study is indispensable in the study of the pathophysiology of neurological disorders. Nevertheless, monolayer systems lack the cytoarchitecture necessary for cellular interactions and neurological disease modeling. Brain organoids generated from human pluripotent stem cells supply an ideal environment to model both cellular interactions and pathophysiology of the human brain. This review article discusses the composition and interactions among neural lineage and non-central nervous system cell types in brain organoids, current studies, and future perspectives in brain organoid research. Ultimately, the promise of brain organoids is to unveil previously inaccessible features of neurobiology that emerge from complex cellular interactions and to improve our mechanistic understanding of neural development and diseases.
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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.