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The organoid modeling approach to understanding the mechanisms underlying neurodegeneration: A comprehensive review.
Neurodegenerative diseases (NDs) are severe disorders of the nervous system, and their causes are still not completely understood. Modeling the complex pathological mechanisms underlying NDs has long posed a significant challenge, as traditional in vitro and animal models often fail to accurately recapitulate the disease phenotypes observed in humans; however, the rise of organoid technology has opened new approaches for developing innovative disease models that can better capture the nuances of the human nervous system. Organoid platforms hold promise for contributing to the design of future clinical trials and advancing our understanding of these devastating neurological conditions and accelerate the discovery of effective, personalized therapies. This comprehensive review discusses the recent advancements in neural organoid technology and explores the potential of patient-derived organoids for modeling NDs conditions and presents findings related to the mechanisms of their development or progress.
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Improved Method for Obtaining Patient-Derived Glioblastoma Organoid and Primary Cells: A Generic and Simplified Approach for Intracranial Tumor With Minimized Input.
INTRODUCTION: Glioblastoma is one of the most malignant primary tumors in adults. The shortages of the traditional tumor models obstruct the development of basic research and therapeutic modes. Application of organoid is critical to keep tumoral heterogeneity and microenvironment. The current method for generating glioblastoma organoid is sophisticated, laborious, and inconvenient. METHODS: We collected glioblastoma tissue samples from patients and used an improved methodology to generate organoids. Subsequently, the collected suspension during the process was used to isolate primary tumor cells. Organoid were used to assess its drug susceptibility. Finally, we generated organoids of other CNS tumors with the same method. RESULTS: The improved method took less time and lowered technical requirements. Glioblastoma organoids generated with our improved method can be cultured for further research. Primary glioblastoma cells isolated from collected medium were proved with immunofluorescence. Patient-derived glioblastoma organoids showed consistent drug susceptibility with the patients. Tumor organoids were also generated successfully from patient's lymphoma and low-grade glioma samples. CONCLUSIONS: We improved an easier and rapider method to generate glioma organoids from tissue samples and avoided wasting primary tumor cells in used medium. This method established a technical foundation for the widely application of organoids in neuro-oncology tumor research and clinical decision-making.
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Laboratory-Engineered Glioblastoma Organoid Culture and Drug Screening.
Glioblastoma (GBM) is described as a group of highly malignant primary brain tumors and stands as one of the most lethal malignancies. The genetic and cellular characteristics of GBM have been a focal point of ongoing research, revealing that it is a group of heterogeneous diseases with variations in RNA expression, DNA methylation, or cellular composition. Despite the wealth of molecular data available, the lack of transferable pre-clinic models has limited the application of this information to disease classification rather than treatment stratification. Transferring the patients' genetic information into clinical benefits and bridging the gap between detailed descriptions of GBM, genotype-phenotype associations, and treatment advancements remain significant challenges. In this context, we present an advanced human GBM organoid model, the Laboratory Engineered Glioblastoma Organoid (LEGO), and illustrate its use in studying the genotype-phenotype dependencies and screening potential drugs for GBM. Utilizing this model, we have identified lipid metabolism dysregulation as a critical milestone in GBM progression and discovered that the microsomal triglyceride transfer protein inhibitor Lomitapide shows promise as a potential treatment for GBM.
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An AI-based segmentation and analysis pipeline for high-field MR monitoring of cerebral organoids.
Cerebral organoids recapitulate the structure and function of the developing human brain in vitro, offering a large potential for personalized therapeutic strategies. The enormous growth of this research area over the past decade with its capability for clinical translation makes a non-invasive, automated analysis pipeline of organoids highly desirable. This work presents a novel non-invasive approach to monitor and analyze cerebral organoids over time using high-field magnetic resonance imaging and state-of-the-art tools for automated image analysis. Three specific objectives are addressed, (I) organoid segmentation to investigate organoid development over time, (II) global cysticity classification and (III) local cyst segmentation for organoid quality assessment. We show that organoid growth can be monitored reliably over time and cystic and non-cystic organoids can be separated with high accuracy, with on par or better performance compared to state-of-the-art tools applied to brightfield imaging. Local cyst segmentation is feasible but could be further improved in the future. Overall, these results highlight the potential of the pipeline for clinical application to larger-scale comparative organoid analysis.
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Organoid-Immune Co-Cultures: A Next-Generation approach to disease modeling.
The incorporation of organoids with immune cells in co-culture systems signifies a groundbreaking advancement in the fields of cancer research and immunology. These three-dimensional models, derived from primary tumor specimens or stem cells, provide a more accurate representation of the tumor microenvironment (TME) than conventional two-dimensional cultures or animal models. This enhanced model allows for a thorough examination of the intricate interactions between cancer cells and the immune system. Although the success rates for organoid initiation can vary, averaging 36.8% across 13 different tumor types, successful organoid establishment enables the co-culture with a variety of immune cells, such as T cells, tumor-infiltrating lymphocytes (TILs), peripheral blood mononuclear cells (PBMCs), macrophages, dendritic cells, and natural killer (NK) cells. This platform enables the study of immune responses to cancer, mechanisms of immune evasion, and the influence of the TME on immune activation and suppression. The review emphasizes research involving intestinal, pancreatic, brain, liver, and cervical organoids, highlighting their role in elucidating disease mechanisms, assessing the effectiveness of immunotherapies (including checkpoint inhibitors and therapeutic vaccines), and conducting preclinical drug evaluations. Notable examples include modeling graft-versus-host disease with intestinal organoids, investigating the influence of DCLK1 on immunosuppression in pancreatic cancer, evaluating the effectiveness of engineered T cells against neuroblastoma using brain organoids, and analyzing the effects of cancer-associated fibroblasts on drug responses in colon cancer. Additionally, the potential of organoids in vaccine development and testing, particularly for influenza and other viral infections, is examined, demonstrating their utility in assessing immune responses and vaccine effectiveness. Despite existing challenges, such as the relatively low efficiency of organoid generation and the complexities involved in fully mimicking the TME, ongoing technological innovations, including tumor-on-chip systems and enhanced matrix materials, are expected to improve the functionality and clinical applicability of these advanced in vitro models.
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Comparative Analysis and Refinement of Human PSC-Derived Kidney Organoid Differentiation with Single-Cell Transcriptomics.
Kidney organoids derived from human pluripotent stem cells have great utility for investigating organogenesis and disease mechanisms and, potentially, as a replacement tissue source, but how closely organoids derived from current protocols replicate adult human kidney is undefined. We compared two directed differentiation protocols by single-cell transcriptomics of 83,130 cells from 65 organoids with single-cell transcriptomes of fetal and adult kidney cells. Both protocols generate a diverse range of kidney cells with differing ratios, but organoid-derived cell types are immature, and 10%-20% of cells are non-renal. Reconstructing lineage relationships by pseudotemporal ordering identified ligands, receptors, and transcription factor networks associated with fate decisions. Brain-derived neurotrophic factor (BDNF) and its cognate receptor NTRK2 were expressed in the neuronal lineage during organoid differentiation. Inhibiting this pathway improved organoid formation by reducing neurons by 90% without affecting kidney differentiation, highlighting the power of single-cell technologies to characterize and improve organoid differentiation.
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Engineering vascularized brain tumor organoids: bridging the gap between models and reality.
Traditional two-dimensional cultures and patient-derived xenografts fail to fully mimic the complexity of the tumor microenvironment, limiting their utility in drug discovery and personalized medicine. Recent breakthroughs in three-dimensional tumor modeling have led to the development of brain tumor organoids, patient-derived organoids, and bioengineered tumor-on-chip systems that offer more physiologically relevant platforms for studying glioblastoma biology and therapeutic response. One of the key advancements in these models is the incorporation of vascular networks to mimic the neurovascular unit and the blood-brain barrier (BBB). Various strategies such as co-culturing with endothelial cells, bio-printing vascularized scaffolds, and utilizing microfluidic platforms have been explored to enhance vascularization within glioblastoma organoids. These models have demonstrated improved nutrient and oxygen exchange, reduced hypoxia, and better maintenance of tumor heterogeneity. However, challenges remain in achieving fully functional capillary networks, BBB integrity, and immune cell integration. This review provides a comprehensive analysis of the latest advancements in brain tumor organoid research, focusing on vascularization strategies, their impact on tumor modeling, and their potential applications in drug screening and personalized therapy. We discussed the strengths and limitations of glioblastoma models, highlighted advanced bioengineering techniques for enhancing organoid complexity, and explored future directions for clinically relevant tumor organoids.
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Modeling Patient-Derived Glioblastoma with Cerebral Organoids.
The prognosis of patients with glioblastoma (GBM) remains dismal, with a median survival of approximately 15 months. Current preclinical GBM models are limited by the lack of a "normal" human microenvironment and the inability of many tumor cell lines to accurately reproduce GBM biology. To address these limitations, we have established a model system whereby we can retro-engineer patient-specific GBMs using patient-derived glioma stem cells (GSCs) and human embryonic stem cell (hESC)-derived cerebral organoids. Our cerebral organoid glioma (GLICO) model shows that GSCs home toward the human cerebral organoid and deeply invade and proliferate within the host tissue, forming tumors that closely phenocopy patient GBMs. Furthermore, cerebral organoid tumors form rapidly and are supported by an interconnected network of tumor microtubes that aids in the invasion of normal host tissue. Our GLICO model provides a system for modeling primary human GBM ex vivo and for high-throughput drug screening.
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A mesh microelectrode array for non-invasive electrophysiology within neural organoids.
Organoids are emerging in vitro models of human physiology. Neural models require the evaluation of functional activity of single cells and networks, which is commonly measured by microelectrode arrays. The characteristics of organoids clash with existing in vitro or in vivo microelectrode arrays. With inspiration from implantable mesh electronics and growth of organoids on polymer scaffolds, we fabricated suspended hammock-like mesh microelectrode arrays for neural organoids. We have demonstrated the growth of organoids enveloping these meshes and the culture of organoids on meshes for up to one year. Furthermore, we present proof-of-principle recordings of spontaneous electrical activity across the volume of an organoid. Our concept enables a new class of microelectrode arrays for in vitro models of three-dimensional electrically active tissue.
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Label-Free Detection of Biochemical Changes during Cortical Organoid Maturation via Raman Spectroscopy and Machine Learning.
Human cerebral organoids have become valuable tools in neurodevelopment research, holding promise for investigating neurological diseases and reducing drug development costs. However, clinical translation and large-scale production of brain organoids face challenges due to invasive methodologies such as immunohistochemistry and omics that are traditionally used for their investigation. These hinder real-time monitoring of organoids and highlight the need for a nondestructive approach to promote resource-efficient production and standardization and enable dynamic studies for drug testing and developmental monitoring. Here, we propose a label-free methodology utilizing Raman spectroscopy (RS) and machine learning to discern cortical organoid maturation stages and to observe their biochemical variations. We validated the method's robustness by analyzing both pluripotent stem cell-derived organoids and embryonic stem cell-derived organoids, revealing also significant biochemical variability between the two. This finding paves the way for the use of RS for longitudinal studies to observe dynamic changes in brain organoids, offering a promising tool for advancing our understanding of brain development and accelerating drug discovery.