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Modeling gliomas with organoids: Classification, fidelity, and guidelines for translational neuro-oncology.
Advances in organoid technology have transformed how gliomas are modeled and studied. Recent FDA and NIH initiatives further promote human-relevant organoid platforms for preclinical research. Glioma organoids can be broadly categorized into 3 main classes: Engineered organoids, which enable controlled modeling of gliomagenesis driven by specific mutations; patient-derived organoids, which preserve key molecular and histopathological features of the original tumors; and assembloids, which are designed to model tumor-microenvironment interactions. Together, these systems provide a human cell-relevant framework for investigating glioma biology, tumor-microenvironment crosstalk, and therapeutic responses and resistance. In this review, we provide a comprehensive overview of the spectrum of glioma organoid models, recognizing that different systems offer distinct and complementary strengths, and we offer practical guidance for selecting appropriate models and analytical readouts based on specific basic and translational research objectives. To address increasing methodological heterogeneity and fragmented terminology, we propose a foundational nomenclature framework for glioma organoid models to improve clarity and communication within the field. We highlight applications in technically challenging subtypes, including isocitrate dehydrogenase (IDH)-mutant gliomas and diffuse midline gliomas (DMGs). We also discuss key challenges-including scalability, standardization, microenvironment fidelity, and vascularization-and emerging innovations addressing these limitations. Finally, we call for greater collaboration and standardization within the glioma organoid community to accelerate the integration of organoid models into translational pipelines to redefine and refine preclinical modeling in neuro-oncology.
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Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning and TDP-43 pathology, extend into frontal, parietal, and temporal areas, pointing to defects across broader cortical regions. The advent of human induced pluripotent stem cell (hiPSC) technology has enabled the generation of human-specific brain cell types in vitro. Here, we provide an overview of the three-dimensional (3D) hiPSC-derived neural organoid platforms used to model cortical structures and to study cortical ALS-associated phenotypes. We review which pathological hallmarks have been recapitulated in these organoids and discuss disease phenotypes reported to date. Further, we comprehensively cover different neural organoid models and experimental strategies, including patient-derived hiPSC models and exogenous pathology induction, while addressing current technical challenges. Together, these advances position neural organoids as an emerging tool to study cell-type-specific and circuit-level mechanisms related to cortical changes in ALS.
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Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens.
Positional patterning during human brain development is orchestrated through highly coordinated interplays of locally produced inductive signals. Although animal models have elucidated general signaling pathways during early neurodevelopment, individual morphogens' effects underlying the proper human brain regionalization remain unclear. Current technologies are limited in generating stable, well-confined gradients in neural organoids for robust regionalization. Here, we report a Matrigel-free passive diffusion-based morphogen gradient generator (PdMG) that reliably established a steep exogenous spatial morphogen gradient in human neural organoids. We further established dorsal-ventral forebrain, rostral-caudal fore-midbrain-like, and rostral-caudal fore-hindbrain-like patterning by applying Sonic hedgehog/Wingless/int1 (WNT) inhibitor, WNT, and retinoic acid gradients, respectively. Spatial transcriptomics analysis revealed robust regionalization in early-stage patterned organoids, as well as active neurogenesis and γ-aminobutyric acid (GABAergic) interneuron migrations in late-stage patterned organoids. Together, this study provides a framework for modeling the spatial-temporal morphogen dynamics that regulate key cell fate specifications and axis formations using patterned neural organoid models.
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Recapitulating Cell-Cell Interactions for Organoid Construction - Are Biomaterials Dispensable?
Cells are spatially patterned in 3D space to allow an intricately orchestrated exchange of signals that regulate their migration, proliferation, differentiation, and death. In recent years cellular self-assembly has emerged as an attractive method to achieve the complexity of organ structures, where the essential cell types co-cultured under carefully defined conditions in vitro have been shown to give rise to organoids such as the optic cup, brain, intestine, liver, and kidney. In view of these developments, what would the revised role of biomaterial-based technologies be, or do they retain any role at all? This Opinion article maintains that biomaterials will not only retain their value but will also synergize with organoid technologies in recapitulating cell-cell interactions.
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Development of Intervertebral Disc Organoids through Directed Differentiation of Mesenchymal Stem Cells and Hierarchical 3D Printing.
Organoid models of early tissue development have been generated for organs such as the brain, kidney, and intestine. However, the development of intervertebral disc (IVD) organoids has rarely been reported. Here, we have developed a protocol to directly differentiate nucleus pulposus (NP) organoids and annulus fibrosus (AF) organoids from human mesenchymal stem cells (hMSCs) using differentiation media supplemented with folic acid (FA) and connective tissue growth factor in a 3D environment. Our findings suggested that FA could potentially promote NP cell generation through modulation of the PI3K-AKT and TGF-β pathways. Utilizing digital light processing 3D printing techniques, we hierarchically constructed biomimetic IVD scaffolds consisting of customized host-guest and silk fibroin hydrogels for NP and AF organoids. Subsequently, we manually assembled IVD scaffolds, NP organoids and AF organoids into complex IVD organoids (IVDOs) exhibiting a central NP-like region surrounded by concentric AF-like structures. Furthermore, the implantation of IVDOs into the goat lumbar spine after discectomy results in anisotropic reconstruction of the IVD. These findings highlight the successful establishment of an in vitro IVD organoid model for future research of disc degenerative diseases and demonstrate a translational therapeutic approach for IVD repair.
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A 3D gut-brain-vascular platform for bidirectional crosstalk in gut-neuropathogenesis.
A 'gut-brain axis' is an intricate bidirectional connection between the gut and the central nervous system, serving as a key pathway for signal exchange. However, current in vitro models do not fully capture these dynamic interactions, limiting mechanistic insight and therapeutic testing. Here, we show a 3D human gut-brain-vascular microphysiological platform that integrates lumenized villus-like intestinal barrier, blood vascular-astrocyte interactions, and brain tissue to model circulation-mediated crosstalk between the gut and brain. Using this system, we demonstrate gut-to-brain signaling by delivering bacterial-derived toxins to the gut compartment, which traverse the gut and neurovascular barriers and trigger neuroinflammatory responses and tau-associated pathology in the brain tissue. Conversely, we show that Alzheimer's- and Parkinson's-relevant stimuli applied to the brain compartment elicit neuroinflammation and disrupt both vascular and intestinal barrier integrity, indicating brain-to-gut feedback. Together, our platform provides a human-relevant tool to dissect mechanisms of bidirectional gut-brain communication and to evaluate therapeutic strategies for neurogastrointestinal disease.
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In vitro organogenesis from pluripotent stem cells.
Pluripotent stem cells (PSCs) have the ability to spontaneously generate structured tissues in vitro reminiscent of embryonic tissue development. Recently, complex organoids such as cortical tissues, cerebral brain organoids, optical cups, intestinal tissues, and liver buds have been generated from PSCs derived from healthy individuals and patients with genetic diseases, providing powerful tools to understand morphogenesis and disease pathology. This article highlights recent advances in the state-of-art generation of organoids from PSCs, possible signaling pathways and mechanisms involved in organogenesis, and the understanding of extracellular microenvironment. Challenges involved in the organoid generation such as increasing organoid size, enhancing the tissue complexity, and improving functional maturation are also discussed.
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Applications of organoid technology to brain tumors.
Lacking appropriate model impedes basic and preclinical researches of brain tumors. Organoids technology applying on brain tumors enables great recapitulation of the original tumors. Here, we compared brain tumor organoids (BTOs) with common models including cell lines, tumor spheroids, and patient-derived xenografts. Different BTOs can be customized to research objectives and particular brain tumor features. We systematically introduce the establishments and strengths of four different BTOs. BTOs derived from patient somatic cells are suitable for mimicking brain tumors caused by germline mutations and abnormal neurodevelopment, such as the tuberous sclerosis complex. BTOs derived from human pluripotent stem cells with genetic manipulations endow for identifying and understanding the roles of oncogenes and processes of oncogenesis. Brain tumoroids are the most clinically applicable BTOs, which could be generated within clinically relevant timescale and applied for drug screening, immunotherapy testing, biobanking, and investigating brain tumor mechanisms, such as cancer stem cells and therapy resistance. Brain organoids co-cultured with brain tumors (BO-BTs) own the greatest recapitulation of brain tumors. Tumor invasion and interactions between tumor cells and brain components could be greatly explored in this model. BO-BTs also offer a humanized platform for testing the therapeutic efficacy and side effects on neurons in preclinical trials. We also introduce the BTOs establishment fused with other advanced techniques, such as 3D bioprinting. So far, over 11 brain tumor types of BTOs have been established, especially for glioblastoma. We conclude BTOs could be a reliable model to understand brain tumors and develop targeted therapies.
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Human Brain Vasculature-on-a-Chip Model Constructed With Microvessels Isolated From Cryopreserved Postmortem Human Brain Tissue.
Brain vasculature is a complex and heterogeneous structure that serves specialized roles in maintaining brain health and homeostasis. There is substantial interest in developing representative human models of the brain vasculature for drug screening and disease modeling applications. Many contemporary strategies have focused on culturing neurovascular cell types in hydrogels and microdevices, but it remains challenging to achieve anatomically relevant vascular structures that have similar function to their in vivo counterparts. Here, we present a strategy for isolating microvessels from cryopreserved human cortical tissue and culturing these vessels in a biomimetic gelatin-based hydrogel contained in a microfluidic device. We provide histological evidence of arteriole and capillary architectures within hydrogels, as well as anastomosis to the hydrogel edges allowing lumen perfusion. In capillaries, we demonstrate restricted diffusion of a 10 kDa dextran, indicating intact passive blood-brain barrier function. We anticipate this bona fide human brain vasculature-on-a-chip will be useful for various biotechnology applications.
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Cyborg Organoids: Implantation of Nanoelectronics via Organogenesis for Tissue-Wide Electrophysiology.
Tissue-wide electrophysiology with single-cell and millisecond spatiotemporal resolution is critical for heart and brain studies. Issues arise, however, from the invasive, localized implantation of electronics that destroys well-connected cellular networks within matured organs. Here, we report the creation of cyborg organoids: the three-dimensional (3D) assembly of soft, stretchable mesh nanoelectronics across the entire organoid by the cell-cell attraction forces from 2D-to-3D tissue reconfiguration during organogenesis. We demonstrate that stretchable mesh nanoelectronics can migrate with and grow into the initial 2D cell layers to form the 3D organoid structure with minimal impact on tissue growth and differentiation. The intimate contact between the dispersed nanoelectronics and cells enables us to chronically and systematically observe the evolution, propagation, and synchronization of the bursting dynamics in human cardiac organoids through their entire organogenesis.