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Glioblastoma Model Using Human Cerebral Organoids.
We have developed a cancer model of gliomas in human cerebral organoids that allows direct observation of tumor initiation as well as continuous microscopic observations. We used CRISPR/Cas9 technology to target an HRasG12V-IRES-tdTomato construct by homologous recombination into the TP53 locus. Results show that transformed cells rapidly become invasive and destroy surrounding organoid structures, overwhelming the entire organoid. Tumor cells in the organoids can be orthotopically xenografted into immunodeficient NOD/SCID IL2RG-/- animals, exhibiting an invasive phenotype. Organoid-generated putative tumor cells show gene expression profiles consistent with mesenchymal subtype human glioblastoma. We further demonstrate that human-organoid-derived tumor cell lines or primary human-patient-derived glioblastoma cell lines can be transplanted into human cerebral organoids to establish invasive tumor-like structures. Our results show potential for the use of organoids as a platform to test human cancer phenotypes that recapitulate key aspects of malignancy.
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The role of endothelial-derived factors in neural tube development: implications for organoid models.
The study of the neural tube (NT), the antecedent structure of the central nervous system, is challenging due to the inaccessibility of the embryo. Thus, our understanding of this crucial timepoint in development is limited. The use of organoid models in recent years has proven immensely beneficial in the field of embryology, allowing the direct study of in vitro models of early neural development. As organoids advance in complexity, the vascularization of brain organoids has become a point of interest due to its significant role in neural development. This raises the question of whether the vascularization of NT organoids is necessary to improve their accuracy. This review summarizes the role of vascularization both during and before NT formation and explores the effects of endothelial-derived factors on this process. While the data indicate that vascularization is essential for proper NT formation, this review also highlights a significant gap in our knowledge and the need to clarify these interactions in order to generate more accurate organoid models.
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CAR-engineered microglia harness phagocytosis to target brain tumor in organoid models.
Glioblastoma (GBM) is among the most aggressive and lethal brain tumors, and standard treatment offers only modest survival benefits. Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic cancers, but its efficacy in GBM remains limited. Here we develop a CAR-engineered microglia (CAR-MG) platform and an organoid-based framework to test whether programmable microglial phagocytosis can be directed against GBM. We isolate microglia (MG) from human cortical organoids and engineer them to express a CAR targeting EGFRvIII, a recurrent tumor-specific EGFR deletion variant in GBM. In a 2D co-culture, CAR-MG selectively eliminates GBM cells through phagocytosis. In a 3D GBM-cortical organoid model, CAR-MG infiltrates tumor sites and depletes GBM cells over extended culture. Single-cell RNA sequencing (scRNA-seq) shows elevated phagocytic pathways in CAR-MG and detects internalized tumor-derived transcripts, which resolve phagocytosis-resistance programs. These results support CAR-MG as a myeloid CAR modality for human brain organoid models.
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Resolving Neurodevelopmental and Vision Disorders Using Organoid Single-Cell Multi-omics.
Human organoid models of the central nervous system, including the neural retina, are providing unprecedented opportunities to explore human neurodevelopment and neurodegeneration in controlled culture environments. In this Perspective, we discuss how the single-cell multi-omic toolkit has been used to identify features and limitations of brain and retina organoids and how these tools can be deployed to study congenital brain malformations and vision disorders in organoids. We also address how to improve brain and retina organoid protocols to revolutionize in vitro disease modeling.
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Brain metastasis organoids: A systematic review of their methods and clinical application.
Brain metastasis represents an ongoing clinical challenge with high morbidity and mortality despite improvements in other areas of oncology. A significant obstacle in brain metastasis research concerns the modelling of the complex tumour-brain microenvironment and there has been a recent shift to the development of more complex assays to improve translational potential. Organoids are three-dimensional tissue aggregates derived from tumour tissue or stem cells and have been utilised extensively in wider biological research. This review aims to summarise the current state of brain metastasis organoid research, with a focus on methodologies, mechanistic understanding, and clinical applicability. A narrative review of the literature was performed using MEDLINE, EMBASE, Scopus, PubMed, ScienceDirect and Web of Science and results were screened using PRISMA guidelines. Search strategies included variations of 'brain metastasis' and 'cerebral organoid' and fifteen articles were included for review. There was a clear lack of uniformity in the methodologies used in organoid production, with additionally fragmented approaches in the investigation of molecular mechanisms and drug discovery. Comparison is thus highly challenging, and this is exacerbated by small sample sizes and diverse primary tumour types. Additionally, there remains an over-reliance on the use of animal-based tissues rather than those derived from human patients. Interestingly, several studies introduced blood-brain-barrier models which show potential however remain in early stages of development. Future studies should aim to streamline organoid production techniques and establish a consensus on relevant molecular pathways of interest, while increasing cohort sizes to enhance clinical applicability. Although it remains in nascent stages, cerebral organoid research represents a field with strong potential to improve knowledge and treatment options for people living with brain metastases.
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Generating Neuroimmune Assembloids Using Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Organoids and Microglia.
The emergence of brain organoids has revolutionized our understanding of neurodevelopment and neurological diseases by providing an in vitro model system that recapitulates key aspects of human brain development. However, conventional organoid protocols often overlook the role of microglia, the resident immune cells of the central nervous system. Microglia dysfunction is implicated in various neurological disorders, highlighting the need for their inclusion in organoid models. Here, we present a novel method for generating neuroimmune assembloids using human-induced pluripotent stem cell (iPSC)-derived cortical organoids and microglia. Building upon our previous work generating myelinating cortical organoids, we extend our methodology to include the integration of microglia, ensuring their long-term survival and maturation within the organoids. We describe two integration methods: one involving direct addition of microglia progenitors to the organoids and an alternative approach where microglia and dissociated neuronal progenitors are aggregated together in a defined ratio. To facilitate downstream analysis, we also describe a dissociation protocol for single-cell RNA sequencing (scRNA-seq) and provide guidance on fixation, cryosectioning, and immunostaining of assembloid structures. Overall, our protocol provides a comprehensive framework for generating neuroimmune assembloids, offering researchers a valuable tool for studying the interactions between neural cell types and immune cells in the context of neurological diseases.
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Engineered neuroglial organoids as living neural interfaces for restorative neurosurgery.
Acute and chronic CNS pathologies that result in tissue loss remain among the most intractable problems in neurosurgery, with current treatments focused on stabilization and neuroprotection rather than structural repair. Neural interfaces such as recording, stimulating, or replacing neural activity have demonstrated value in restoring function via prostheses and brain-computer interfaces, yet these approaches are constrained by electrode design, bandwidth, and limited biological integration. Engineered neuroglial organoids offer a complementary, biologically based interface strategy. Derived from pluripotent stem cells, neuroglial organoids arrive as 3D constructs containing neurons and glia in intrinsic architecture, capable of vascularization, synaptic connectivity, and integration with host tissue. Building on dissociated stem cell suspensions, organoids act not only as reservoirs of cells but also as living neural interfaces, receiving inputs from host circuits and generating functional outputs. Preclinical studies have demonstrated that transplanted organoids can couple to host sensory pathways, respond to stimulation, and support recovery of motor and cognitive functions. Moreover, emerging work coupling organoid grafts to brain-computer interfaces highlights the potential for closed-loop biological electronic systems, in which engineered devices provide precise recording and stimulation while organoids contribute adaptive, active biological circuits. This combination allows real-time bidirectional communication, allowing the graft to be both monitored and adapted to structurally and functionally integrate into host tissue. In this review, the authors examine neuroglial organoid transplantation through the lens of neural interfacing. They outline lessons from non-CNS organoid transplantation, summarize neurotrauma studies where grafts engage host circuits, and highlight opportunities to integrate organoids with electrodes, stimulation paradigms, and computational models. They also discuss challenges, namely vascularization, immune tolerance, surgical delivery, and manufacturing standards, that parallel those in neural device translation. For neurosurgeons, the appeal of neuroglial organoids lies not only in tissue replacement but in establishing a new class of biological neural interfaces, extending the reach of restorative neurosurgery. By merging living constructs with engineered devices, organoid-based strategies may enable hybrid restorative systems that restore function after neurological injury and disease.
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Wnt-YAP interactions in the neural fate of human pluripotent stem cells and the implications for neural organoid formation.
Human pluripotent stem cells (hPSCs) have shown the ability to self-organize into different types of neural organoids (e.g., whole brain organoids, cortical spheroids, midbrain organoids etc.) recently. The extrinsic and intrinsic signaling elicited by Wnt pathway, Hippo/Yes-associated protein (YAP) pathway, and extracellular microenvironment plays a critical role in brain tissue morphogenesis. This article highlights recent advances in neural tissue patterning from hPSCs, in particular the role of Wnt pathway and YAP activity in this process. Understanding the Wnt-YAP interactions should provide us the guidance to predict and modulate brain-like tissue structure through the regulation of extracellular microenvironment of hPSCs.
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Bioengineering tools for next-generation neural organoids.
Human stem cell-derived neural organoids were recently introduced as powerful in vitro 3D experimental model systems that innately undergo critical steps of organogenesis in culture and exhibit molecular, cellular, and structural features similar to the fetal human nervous system. These organoids have yielded new insights into human neurodevelopment and associated disorders. However, neural organoids have some crucial limitations that arise from the loosely controlled conditions for their development, an inability to maintain their spatial orientation in culture and a lack of technologies for taking long-term measurements on their morphology and electrical activity. Here, we review recent progress in using bioengineering methods to improve neural organoid formation and analysis by leveraging microfabrication, biomaterials, 3D printing, and flexible electrodes. We discuss how the applications of each technique can help to address critical limitations with standard neural organoid models. We conclude with a perspective on future applications of bioengineered next-generation neural organoids.
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Optimizing GBM organoid construction with hydrogel-based models: GelMA-HAMA scaffold supports GBM organoids with clonal growth for drug screening.
Adult glioblastoma (GBM) is a highly malignant tumor with a poor prognosis and high mortality rate. As versatile 3D culture systems in vitro, organoid models are emerging as a promising new tool for GBM research and combat. However, Matrigel, the most used extracellular matrix, is animal-derived with a complex composition and significant batch-to-batch variability, requiring further optimization for GBM organoid construction. Hydrogels, high-affinity polymers, have been widely employed in organoid construction for their customizable properties. In the present study, we selected and tested several commonly used hydrogel materials-hyaluronic acid methacryloyl (HAMA), chitosan methacryloyl (CSMA), and gelatin methacryloyl (GelMA)-for the construction of GBM organoids. To address the limitations of a single Matrigel, we combined Matrigel with different hydrogels and found that hydrogels influenced glioblastoma stem cells and organoid formation in distinct ways. Matrigel-HAMA (MH) promoted the formation of independent spherical clones but with a significantly lower glioblastoma stem cell (GSC) proliferation rate. GelMA-HAMA(GH) could replace Matrigel preserving the characteristics and proliferative capacity of GSCs and supported the formation of more compact spherical clones than MH did. Further experimentation with ribosomal inhibitor CX5461 and CX5461 + IFNβ indicated that GH-based GBM organoid model constituted an efficient system for GBM drug testing, discovery, and precision medicine.