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Organoids as next-generation models for investigating intracranial tumours.
Tumour organoids have emerged as important tools in brain tumour research, addressing long-standing limitations of conventional two-dimensional cultures, xenograft models, and genetically engineered mouse models. By preserving patient-specific genetic alterations, cellular diversity, spatial architecture, and key microenvironmental features, organoid systems enable more faithful modelling of tumour biology across a broad range of intracranial tumours, including gliomas, meningiomas, medulloblastomas, pituitary tumours, and craniopharyngiomas. Patient-derived organoids, genetically engineered models, co-culture systems, and bioprinted platforms have collectively advanced understanding of tumour initiation, invasion, heterogeneity, and therapeutic resistance, while offering clinically relevant systems for drug screening and personalised therapy prediction. Importantly, organoid models facilitate mechanistic interrogation of tumour-microenvironment interactions that are difficult to capture in other systems, including neural-tumour crosstalk, vascular niche formation, and immune modulation. Their compatibility with high-throughput screening and integration with emerging technologies, such as single-cell and spatial omics, CRISPR-based genome editing, microfluidics, and artificial intelligence, has further expanded their utility for functional genomics, biomarker discovery, and predictive modelling of treatment response. The development of large-scale organoid biobanks that represent diverse tumour subtypes and patient populations also provides critical infrastructure for reproducible research and collaborative precision oncology efforts. While challenges remain, including variability in culture protocols, incomplete immune and vascular representation, and barriers related to cost and technical complexity, ongoing methodological innovations are progressively enhancing the physiological fidelity and translational relevance of organoid systems. Overall, tumour organoids represent a promising interface between experimental research and clinical application in neuro-oncology, with significant potential to accelerate therapeutic discovery, refine patient stratification, and ultimately improve outcomes for individuals with brain tumours.
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Organoid models for chemosensing cell studies.
Over the past decade, tremendous progress has been made in using organoids-three-dimensional, miniature organ-like structures-to model tissues and organs in vitro, including both regenerative tissues (which contain tissue-residing stem/progenitor cells) and largely nonregenerative tissues, such as the brain. Organoids resemble the tissues from which they are derived in many aspects of structure, function, and organization. As a result, organoid models have been used in a variety of fields for cell studies. Many well-written reviews have provided in-depth descriptions of organoid models for various systems. In this article, we review the establishment and application of tissue stem/progenitor cell-derived organoid models relevant to chemosensory cell studies (taste and smell) and discuss the limitations and future directions of using these models to study chemosensation.
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Morphogenetic Designs, and Disease Models in Central Nervous System Organoids.
Since the emergence of the first cerebral organoid (CO) in 2013, advancements have transformed central nervous system (CNS) research. Initial efforts focused on studying the morphogenesis of COs and creating reproducible models. Numerous methodologies have been proposed, enabling the design of the brain organoid to represent specific regions and spinal cord structures. CNS organoids now facilitate the study of a wide range of CNS diseases, from infections to tumors, which were previously difficult to investigate. We summarize the major advancements in CNS organoids, concerning morphogenetic designs and disease models. We examine the development of fabrication procedures and how these advancements have enabled the generation of region-specific brain organoids and spinal cord models. We highlight the application of these organoids in studying various CNS diseases, demonstrating the versatility and potential of organoid models in advancing our understanding of complex conditions. We discuss the current challenges in the field, including issues related to reproducibility, scalability, and the accurate recapitulation of the in vivo environment. We provide an outlook on prospective studies and future directions. This review aims to provide a comprehensive overview of the state-of-the-art CNS organoid research, highlighting key developments, current challenges, and prospects in the field.
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Gene-Edited Fluorescent and Mixed Cerebral Organoids.
Cerebral organoids are a promising model to study human brain function and disease, although the high inter-organoid variability is still challenging. To overcome this limitation, we introduce the method of labeled mixed organoids generated from two different human induced pluripotent stem cell (hiPSC) lines, which enables the identification of cells from different origin within a single organoid. The method combining gene editing and organoid differentiation offers a unique tool to study gene function in a complex human three-dimensional model. Using a CRISPR-Cas9 gene-editing approach, different fluorescent proteins were fused to β-actin or lamin B1 in hiPSCs, and mixtures of differently edited cells were seeded to induce cerebral organoid differentiation. Consequently, the development of the organoids was detectable by live confocal fluorescence microscopy of whole organoids and immunofluorescence staining in fixed samples. We demonstrate that a direct comparison of the individual cells is possible by having the edited and the control (or the two differentially labeled) cells within the same organoid, thus overcoming the inter-organoid inhomogeneity limitations. Furthermore, the approach enables mosaic analysis of mutant clones in a wild-type three-dimensional cellular environment. It paves the way for the reliable analysis of human genetic disorders using organoids and the gain of fundamental understanding of the molecular mechanisms underlying pathological conditions.
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Developing a Multidisciplinary Approach for Engineering Stem Cell Organoids.
Recent advances in stem cell biology, synthetic biology, bioengineering, and biotechnology have included significant work leading to the development of stem cell-derived organoids. The growing popularity of organoid research and use of organoids is widely due to the fact that these three-dimensional cellular structures better model human physiology compared to traditional in vitro and in vivo methods by recapitulating many biologically relevant parameters. Organoids show great promise for a wide range of applications, such as for use in disease modeling, drug discovery, and regenerative medicine. However, many challenges associated with reproducibility and scale up still remain. Identification of the conditions which generate a robust environment that predictably promotes cellular self-assembly and organization leading to organoid formation is critical and requires a multidisciplinary approach. To accomplish this we need to identify a cellular source, engineer a matrix to stimulate cell-cell and cell-matrix interactions, and provide the biochemical and biophysical cues which mimic that of the in vivo environment. Discussion of the components needed for organoid development and formation is reviewed herein, as well as specific organoid examples and the promise of this research for the future.
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Maintaining Human Glioblastoma Cellular Diversity Ex vivo using Three-Dimensional Organoid Culture.
Glioblastoma (GBM) is the most commonly occurring primary malignant brain cancer with an extremely poor prognosis. Intra-tumoral cellular and molecular diversity, as well as complex interactions between tumor microenvironments, can make finding effective treatments a challenge. Traditional adherent or sphere culture methods can mask such complexities, whereas three-dimensional organoid culture can recapitulate regional microenvironmental gradients. Organoids are a method of three-dimensional GBM culture that better mimics patient tumor architecture, contains phenotypically diverse cell populations, and can be used for medium-throughput experiments. Although three-dimensional organoid culture is more laborious and time-consuming compared to traditional culture, it offers unique benefits and can serve to bridge the gap between current in vitro and in vivo systems. Organoids have established themselves as invaluable tools in the arsenal of cancer biologists to better understand tumor behavior and mechanisms of resistance, and their applications only continue to grow. Here, details are provided about methods for generating and maintaining GBM organoids. Instructions of how to perform organoid sample embedding and sectioning using both frozen and paraffin-embedding techniques, as well as recommendations for immunohistochemistry and immunofluorescence protocols on organoid sections, and measurement of total organoid cell viability, are all also described.
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Organoid-based models in cerebrovascular disorders: Mechanistic insights and precision medicine.
Cerebrovascular diseases are the leading cause of death and long-term disability worldwide, including ischemic stroke, intracerebral hemorrhage, intracranial aneurysms, and cerebrovascular malformations, imposing a heavy burden on society and families. Organoid technology, as a major breakthrough in the field of biomedicine, provides a new platform for the study of cerebrovascular diseases. By constructing organoid-based models of cerebrovascular diseases, researchers can simulate their pathogenesis in vitro and deeply explore key links such as angiogenesis and neurovascular unit interactions, providing a new platform for the early diagnosis of the diseases, the discovery of treatment targets, and drug development. This review summarizes the current progress of organoid technology in cerebrovascular disease research, focusing on model establishment and mechanistic investigations of disorders such as cerebral cavernous malformations, ischemic stroke, and hemorrhagic stroke. Furthermore, we discuss the potential applications and current limitations of organoid platforms in disease modeling, drug screening, and future translational research. Although organoid technology holds promise for advancing precision medicine, further optimization, validation, and integration with clinical studies are required before broader clinical applications can be realized.
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Enhanced Neuronal Activity and Asynchronous Calcium Transients Revealed in a 3D Organoid Model of Alzheimer's Disease.
Advances in the development of three-dimensional (3D) brain organoids maintained in vitro have provided excellent opportunities to study brain development and neurodegenerative disorders, including Alzheimer's disease (AD). However, there remains a need to generate AD organoids bearing patient-specific genomic backgrounds that can functionally recapitulate the key features observed in the AD patient's brain. To address this need, we described a strategy to generate self-organizing 3D cerebral organoids which develop a functional neuronal network connectivity. This was achieved by neuroectoderm induction of human pluripotent stem cell (hPSCs) aggregates and subsequent differentiation into desired neuroepithelia and mature neurons in a 3D Matrigel matrix. Using this approach, we successfully generated AD cerebral organoids from human pluripotent stem cells (hPSCs) derived from a familial AD patient with a common mutation in presenilin 2 (PSEN2N141I). An isogenic control with an identical genetic background but wild-type PSEN2 was generated using CRISPR/Cas9 technology. Both control and AD organoids were characterized by analyzing their morphology, the Aβ42/Aβ40 ratio, functional neuronal network activity, drug sensitivity, and the extent of neural apoptosis. The spontaneous activity of the network and its synchronization was measured in the organoids via calcium imaging. We found that compared with the mutation-corrected control organoids, AD organoids had a higher Aβ42/Aβ40 ratio, asynchronous calcium transients, and enhanced neuronal hyperactivity, successfully recapitulating an AD-like pathology at the molecular, cellular, and network level in a human genetic context. Moreover, two drugs which increase neuronal activity, 4-aminopyridine (4-AP) and bicuculline methochloride, induced high-frequency synchronized network bursting to a similar extent in both organoids. Therefore, our study presents a promising organoid-based biosystem for the study of the pathophysiology of AD and a platform for AD drug development.
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Breast cancer brain metastasis: evaluating the effectiveness of alginate-based organoids in metastasis modeling to replace matrigel.
BACKGROUND: One of the most important and devastating side effects of breast cancer is brain metastasis. Our understanding of cancer heterogeneity is revolutionized by tumoral organoids and seems promising for personalized medicine. This study aimed to generate a hydrogel-based brain metastasis organoid. METHODS: Mouse brain metastatic tumor cells (4T1B) were isolated and cultured from the brain metastasis lesions of mice with breast cancer. Different hydrogels, including alginate, carboxymethylcellulose, gelatin, collagen, and matrigel, were prepared. Pre-coated hydrogels in 96-well plates were treated with 4T1B cells. The morphology and viability of metastatic organoids were analyzed after 7 days. RESULTS: According to our results, 4T1B cells formed semi-regular cluster structures in alginate hydrogel. In this group, the cell survival rate and formation of three-dimensional structures were significantly higher than in other groups. CONCLUSION: For organoid cultures, there's a lot of research on natural and synthetic scaffolds that are chemically or mechanically well-designed. In the present study, we used highly brain metastatic tumor cells and detected that alginate hydrogel is the best choice for organoid formation and breast cancer brain metastasis modeling.
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Patient-derived cancer organoids for drug screening: Basic technology and clinical application.
Cancer organoids, a three-dimensional (3D) culture system of cancer cells derived from tumor tissues, recapitulate physiological structure of the parental tumor. Different tumor organoids have been established for a variety of tumor types, such as colorectal, liver, stomach, pancreatic and brain tumors. Some tumor organoid biobanks are built to screen and discover novel antitumor drug targets. Moreover, patients-derived tumor organoids (PDOs) could predict treatment response to chemoradiotherapy, targeted therapy and immunotherapy to provide guidance for personalized cancer therapy. In this review, we provide an updated overview of tumor organoid development, summarize general approach to establish tumor organoids, and discuss the application of anti-cancer drug screening based on tumor organoid and its application in personalized therapy. We also outline the opportunities and challenges for organoids to guide precision medicine.