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Page 17 of 545-
Mapping Thyroid Hormone Action in the Human Brain.
Background: Normal brain development, mood, and cognitive functions depend on thyroid hormone (TH) action. However, little is known about how TH mediates its actions in the human brain. This is due to limited access to human brains deprived of TH during fetal and early postnatal life, as well as from adults with altered thyroid status. One way to partially bypass these limitations is by using magnetic resonance imaging and spectroscopy, two neuroimaging techniques that provide detailed, noninvasive information on human brain structure and function. Another way is using human-induced pluripotent stem cell (hiPSCs)-derived three-dimensional in vitro systems, known as brain organoids, which allow for the study of fundamental aspects of the early stages of human brain development. Summary: This narrative review focuses on neuroimaging and brain organoid studies. Neuroimaging of human brains performed in individuals with different thyroid conditions provides information on the volume, myelination, blood flow, neural activity, and connectivity of different areas. Such studies show that suboptimal thyroid status can impact human brain development and its normal function throughout life. This is true not only for patients with sporadic congenital hypothyroidism, during pregnancy or early after birth, but also for adult patients with hypo- or hyperthyroidism, patients carrying mutations that manifest as impaired sensitivity to TH, and even for normal individuals during aging. Studies using brain organoids generated from hiPSCs of healthy individuals or patients with thyroid genetic conditions provide insights into how TH can impact the early development of the human cerebral cortex. Conclusions: The developmental alterations in children born to mothers with different degrees of gestational hypothyroidism or who developed hypothyroidism early in life are remarkable, affecting multiple brain regions and pathways, including the cerebral cortex, hippocampus, cerebellum, interhemispheric and corticospinal tracts, and associative nuclei. The data connecting such changes to poor neurological outcomes in adult patients with hypothyroidism represent an objective link between thyroid-specific functional brain alterations and behavior. Growing brain organoids require TH, which is critical for human neurogenesis and oligodendrogenesis. These models have proven useful in screening drugs with potential therapeutic effects for patients with genetic thyroid diseases.
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Emerging Bioelectronics for Brain Organoid Electrophysiology.
Human brain organoids are generated from three-dimensional (3D) cultures of human induced pluripotent stem cells and embryonic stem cells, which partially replicate the development and complexity of the human brain. Many methods have been used to characterize the structural and molecular phenotypes of human brain organoids. Further understanding the electrophysiological phenotypes of brain organoids requires advanced electrophysiological measurement technologies to achieve long-term stable 3D recording over the time course of the organoid development with single-cell, millisecond spatiotemporal resolution. In this review, first, we briefly introduce the development, generation, and applications of human brain organoids. We then discuss the conventional methods used for characterizing the morphological, genetic, and electrical properties of brain organoids. Next, we highlight the need for characterizing electrophysiological properties of brain organoids in a minimally invasive manner. In particular, we discuss recent advances in the multi-electrode array (MEA), 3D bioelectronics, and flexible bioelectronics and their applications in brain organoid electrophysiological measurement. In addition, we introduce the recently developed cyborg organoids platform as an emerging tool for the long-term stable 3D characterization of the brain organoids electrophysiology at high spatiotemporal resolution. Finally, we discuss the perspectives of new technologies that could achieve the high-throughput, multimodal characterizations from the same brain organoids.
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Robust Tissue Fabrication for Long-Term Culture of iPSC-Derived Brain Organoids for Aging Research.
The currently available animal and cellular models do not fully recapitulate the complexity of changes that take place in the aging human brain. A recent development of procedures describing the generation of human cerebral organoids, derived from human induced pluripotent stem cells (iPSCs), has the potential to fundamentally transform the ability to model and understand the aging of the human brain and related pathogenic processes. Here, an optimized protocol for generating, maintaining, aging, and characterizing human iPSC-derived cerebral organoids is presented. This protocol can be implemented to generate brain organoids in a reproducible manner and serves as a step-by-step guide, incorporating the latest techniques that result in improved organoid maturation and aging in culture. Specific issues related to organoid maturation, necrosis, variability, and batch effects are being addressed. Taken together, these technological advances will allow the modeling of brain aging in organoids derived from a variety of young and aged human donors, as well as individuals afflicted with age-related brain disorders, allowing the identification of physiologic and pathogenic mechanisms of human brain aging.
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Lineage Recording in Human Brain Organoids with iTracer.
Induced pluripotent stem cell (iPSC)-derived organoids provide models to study human organ development. Single-cell transcriptomics enables highly resolved descriptions of cell states within these systems; however, approaches are needed to directly determine the lineage relationship between cells. Here we provide a detailed protocol (Fig. 1) for the application of iTracer (He Z, Maynard A, Jain A, et al., Nat Methods 19:90-99, 2022), a recently published lineage recorder that combines reporter barcodes with inducible CRISPR-Cas9 scarring and is compatible with single-cell and spatial transcriptomics. iTracer is used to explore clonality and lineage dynamics during brain organoid development. More broadly, iTracer can be adapted to any iPSC-derived culture system to dissect lineage dynamics during normal or perturbed development.
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Modeling hereditary diffuse leukoencephalopathy with axonal spheroids using microglia-sufficient brain organoids.
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare, fatal, adult-onset neurodegenerative disease that is most often caused by mutations affecting the colony stimulating factor-1 receptor (CSF-1R). To understand how CSF-1R-mutation affects human microglia - the specialized brain-resident macrophages of the central nervous system - and the downstream consequences for neuronal cells, we used a macrophage and forebrain organoid co-culture system based on induced pluripotent stem cells generated from two patients with HDLS, with CSF-1R gene-corrected isogenic organoids as controls. Macrophages derived from iPSC (iMacs) of patients exhibited a metabolic shift toward the glycolytic pathway and reduced CSF-1 sensitivity, which was associated with higher levels of IL-1β production and an activated inflammatory phenotype. Bulk RNA sequencing revealed that iMacs adopt a reactive state that leads to impaired regulation of neuronal cell populations in organoid cultures, thereby identifying microglial dysregulation and specifically IL-1β production as key contributors to the degenerative neuro-environment in HDLS.
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Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids.
Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases.
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Deciphering brain organoid heterogeneity by identifying key quality determinants.
Brain organoids derived from human pluripotent stem cells (hPSCs) hold immense potential for modeling neurodevelopmental processes and disorders. However, their experimental variability and undefined organoid selection criteria for analysis hinder reproducibility. As part of the Bavarian ForInter consortium, we generated 72 brain organoids from distinct hPSC lines. We conducted a comprehensive analysis of their morphological and cellular characteristics at an early stage of their development. In our assessment, the Feret diameter emerged as a reliable, single parameter that characterizes brain organoid quality. Transcriptomic analysis of our organoid identified the abundance of unintended mesodermal differentiation as a major confounder of unguided brain organoid differentiation, correlating with Feret diameter. High-quality organoids consistently displayed a lower presence of mesenchymal cells. These findings provide a framework for enhancing brain organoid standardization and reproducibility, underscoring the need for morphological quality controls and considering the influence of mesenchymal cells on organoid-based modeling.
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Advances in cellular and structural engineering of brain organoids for disease modeling: A Comprehensive Review.
BACKGROUND: Organoid technology has rapidly evolved as a transformative tool for modeling human physiology and disease. Organoids are three-dimensional, stem cell-derived constructs that self-organize to recapitulate key structural and functional features of native organs. Among known organoids, brain organoids have provided unprecedented insights into human neurodevelopment and pathophysiology, overcoming the limitations of traditional two-dimensional cultures and animal models. These models closely mimic the architecture, cellular diversity, and regional specification of the human brain, offering a physiologically relevant platform for mechanistic studies. Therefore, brain organoids have become indispensable for investigating complex neurological disorders, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. AIM OF THE REVIEW: This review aims to discuss recent advancements in brain organoid technology, emphasizing innovations in each component of the system: cells, supporting cells, three-dimensional architecture, and microenvironment, particularly in the context of major neurological diseases. KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Notably, brain organoids provide valuable platforms for understanding molecular mechanisms, identifying therapeutic targets, and evaluating drug responses by preserving patient-specific genetic backgrounds and faithfully recapitulating disease-associated phenotypes. Meanwhile, advances in transcriptomic profiling, vascularization strategies, region-specific induction, and CRISPR/Cas9-based genetic engineering have further enhanced the utility and reproducibility of these techniques. This review summarizes key technological advancements and major findings in brain organoid research, including microenvironmental modulation, high-throughput culture platforms, and integrative analysis tools. We also highlight the associated applications in disease modeling, drug screening, and personalized medicine, while addressing current limitations and ethical considerations. As brain organoid systems continue to mature, through innovations such as assembloids, vascular integration, and patient-derived modeling, these systems offer great promise for bridging the translational gap in neuroscience and neurotherapeutics between bench and bedside.
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Chimeric human organoid and mouse brain slice co-cultures to study microglial function.
Studying the dynamic role of microglia in brain development and neurodegenerative diseases requires models that closely resemble the human brain environment. While human induced pluripotent stem cell (iPSC)-derived organoids (hORGs) effectively reproduce key neuronal and certain glial cell types, modeling human microglia in vitro remains challenging. Inspired by recent approaches demonstrating enhanced microglial maturation in hORGs transplanted into mouse brains, we develop a chimeric model by co-culturing hORGs with mouse brain slice cultures (mBSCs). This system reveals cross-species interactions associated with an earlier onset of cortical neuronal differentiation markers in the hORGs. Human iPSC-derived microglia, pre-differentiated in mBSCs, migrate into the hORGs and adopt ramified morphology. They remain viable for several months and respond to laser-induced injury, demonstrating long-term functionality. This in vitro model supports long-term study of human microglia in a brain-like environment, providing a platform for mechanistic studies and screening compounds that target microglial function.
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Organoids for modeling prion diseases.
Human cerebral organoids are an exciting and novel model system emerging in the field of neurobiology. Cerebral organoids are spheres of self-organizing, neuronal lineage tissue that can be differentiated from human pluripotent stem cells and that present the possibility of on-demand human neuronal cultures that can be used for non-invasively investigating diseases affecting the brain. Compared with existing humanized cell models, they provide a more comprehensive replication of the human cerebral environment. The potential of the human cerebral organoid model is only just beginning to be elucidated, but initial studies have indicated that they could prove to be a valuable model for neurodegenerative diseases such as prion disease. The application of the cerebral organoid model to prion disease, what has been learned so far and the future potential of this model are discussed in this review.