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Page 59 of 545-
Human Cerebral Organoids Reveal Early Spatiotemporal Dynamics and Pharmacological Responses of UBE3A.
Angelman syndrome is a complex neurodevelopmental disorder characterized by delayed development, intellectual disability, speech impairment, and ataxia. It results from the loss of UBE3A protein, an E3 ubiquitin ligase, in neurons of the brain. Despite the dynamic spatiotemporal expression of UBE3A observed in rodents and the potential clinical importance of when and where it is expressed, its expression pattern in humans remains unknown. This reflects a common challenge of studying human neurodevelopment: prenatal periods are hard to access experimentally. In this work, human cerebral organoids reveal a change from weak to strong UBE3A in neuronal nuclei within 3 weeks of culture. Angelman syndrome human induced pluripotent stem cell-derived organoids also exhibit early silencing of paternal UBE3A, with topoisomerase inhibitors partially rescuing UBE3A levels and calcium transient phenotypes. This work establishes human cerebral organoids as an important model for studying UBE3A and motivates their broader use in understanding complex neurodevelopmental disorders.
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Generating 3D mouse organoids for cortex development and evo-devo.
How do ci-regulatory differences, across mouse subspecies and over evolutionary timescales, shape cell-type specification and maturation during corticogenesis? In this issue of Developmental Cell, Medina-Cano et al. establish a scalable mouse organoid platform that recapitulates developmental dynamics and enables mapping of allele-specific expression, linking cis-regulatory variation with neurodevelopmental mechanisms and disease-associated genetics.
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Spatiotemporal Expression of IRS-1 During Brain Development and its Role in Neural Stem Cell Differentiation.
Insulin receptor substrate 1 (IRS-1) is a key mediator of insulin signaling linked to focal cortical dysplasia. While previous studies have primarily focused on IRS-1 in peripheral tissues, its function in the central nervous system has remained largely unexplored. This study aimed to investigate the spatiotemporal expression patterns of IRS-1 protein in mouse cerebral cortex and human brain organoids, along with its role in neural development. In mice, Irs-1 expression was consistent throughout brain development, with notable localization in the ventricular/subventricular zone during early gestation and later in the outer cerebral cortex. In human brain organoids, IRS-1 was primarily found in rosette structures initially, shifting to the outer cortical layer as they matured. Knockdown of Irs-1 at embryonic day 14.5 via in-utero electroporation impaired neuronal migration, resulting in more neurons remaining in the intermediate zone compared to controls. Moreover, SH-SY5Y cells treated with isotretinoin exhibited a significant decrease in IRS-1 protein expression during maturation. RNA sequencing indicates an upregulation of neurodevelopment-related genes alongside a downregulation of the IRS-1. These findings underscore the significance of IRS-1 in brain development, particularly regarding neuronal migration and differentiation.
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Development of neuronal timescales in human cortical organoids and rat hippocampus dissociated cultures.
To support complex cognition, neuronal circuits must integrate information across multiple temporal scales, ranging from milliseconds to decades. Neuronal timescales describe the duration over which activity within a network persists, posing a putative explanatory mechanism for how information might be integrated over multiple temporal scales. Little is known about how timescales develop in human neural circuits or other model systems, limiting insight into how the functional dynamics necessary for cognition emerge. In our work, we show that neuronal timescales develop in a nonlinear fashion in human cortical organoids, which is partially replicated in dissociated rat hippocampus cultures. We use spectral parameterization of spiking activity to extract an estimate of neuronal timescale that is unbiased by coevolving oscillations. Cortical organoid timescales begin to increase around month 6 postdifferentiation. In rodent hippocampal dissociated cultures, we see that timescales decrease from in vitro days 13-23 before stabilizing. We speculate that cortical organoid development over the duration studied here reflects an earlier stage of a generalized developmental timeline in contrast to the rodent hippocampal cultures, potentially accounting for differences in timescale developmental trajectories. The fluctuation of timescales might be an important developmental feature that reflects the changing complexity and information capacity in developing neuronal circuits.NEW & NOTEWORTHY Neuronal timescales describe the persistence of activity within a network of neurons. Timescales were found to fluctuate with development in two model systems. In cortical organoids timescales increased, peaked, and then decreased throughout development; in rat hippocampal dissociated cultures timescales decreased over development. These distinct developmental models overlap to highlight a critical window in which timescales lengthen and contract, potentially indexing changes in the information capacity of neuronal systems.
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Neurodegenerative brain models vs. cell replacement or restoration therapy: A review on promises and pitfalls.
Disease models have proven useful tools for gaining deeper mechanistic insights into neurodegenerative diseases. In this context, stem cell technology is effective, especially induced pluripotent stem cell (iPSC)-derived brain organoids and cell replacement/restoration which can be used for personalized medicine, allowing physicians to test the efficacy of drugs in vitro before delivering them to patients, enabling more precise and personalized treatment. Nonetheless, it offers the potential to minimize (or even eliminate) the use of animals, provides important clues for disease processes, and accelerates therapeutic strategies. Perhaps in the not-too-distant future, organoid models of the human brain will be able to link blood-brain barrier cultures with other liver cultures, simulating blood flow across organs and as a method of testing medicines, giving crucial pharmacokinetics and pharmacodynamics data. Simultaneously, stem cell interventions for cell replacements or restoration therapy would enable us to realize efficacious and realistic therapeutic options for Neurodegenerative diseases.
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Mechanical impact on neural stem cell lineage decisions in human brain organoids.
During neurodevelopment neural stem cells give rise to a spatially patterned tissue in which a regionally differentially regulated balance between proliferation and differentiation produces the fine-tuned number of neurons and macroglia necessary for a functional central nervous system. The cells driving these highly intricated developmental processes of patterning, growth and differentiation are constantly exposed to a mechanical environment that is, however, variable between different brain regions and along differentiation trajectories. Here we demonstrate that both, acute mechanical manipulations as well as a persistent change in the mechanical environment provided to human brain organoids, instruct neural stem cell lineage decisions. Furthermore, we dissect the underlying changes in the molecular program of organoid-resident cells by bulk- and single cell RNA-sequencing. These data reveal that mechanical manipulations impact on molecular programs governing early patterning events as well as cell-type-specific cellular metabolism. Thus, our results unravel a regulatory network linking mechanics and neural stem cell lineage decisions.
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Perfluorooctane sulfonate (PFOS) exposure alters developmental and metabolic gene expression in human hippocampal organoids.
Perfluorooctane sulfonate (PFOS), a persistent member of the per- and polyfluoroalkyl substances (PFAS), has been associated with adverse neurodevelopmental outcomes. However, the direct effects of PFOS on the developing human hippocampus remain incompletely understood due to the limited availability of physiologically relevant human models. In the present study, we utilized human hippocampal organoids (hHOs) derived from human pluripotent stem cells to investigate the developmental effects of PFOS exposure. The organoids exhibited molecular characteristics consistent with hippocampal identity, including increased expression of the medial pallium-associated markers compared with human cortical organoids. Exposure to PFOS resulted in a dose-dependent reduction in MAP2 immunoreactivity together with increased cleaved caspase-3-positive cells, suggesting neuronal toxicity. Gene expression analyses further demonstrated increased expression of progenitor-associated genes accompanied by reduced expression of neuronal markers DCX and MAP2. Bulk RNA sequencing identified broad transcriptional alterations following PFOS exposure, including enrichment of proliferation-associated biological processes and downregulation of neuronal differentiation-related pathways. In addition, multiple genes involved in mitochondrial oxidative phosphorylation and the tricarboxylic acid cycle were reduced in PFOS-treated organoids. Collectively, these findings suggest that PFOS induces neuronal toxicity in human hippocampal organoids and is accompanied by alterations in developmental transcriptional programs and mitochondrial metabolism-related gene expression.
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Quick and robust method for the generation of human iPSC-derived choroid plexus organoids.
The choroid plexus (ChP) is a key brain structure responsible for cerebrospinal fluid (CSF) production and forms a selective barrier that regulates brain homeostasis and immune surveillance. In vitro models of ChP are essential for studying CSF dynamics, viral entry, neuroinflammation, and CNS drug transport; yet current organoid protocols remain complex, slow, and difficult to reproduce. Here, we report a quick and robust method for the generation of human iPSC-derived ChP organoids that is xeno-free and serum-free, scalable, and reproducible. Early GSK3β inhibition and transient WNT modulation guide organoids toward cystic ChP-enriched structures, confirmed by ventricle-like morphology, and expression of canonical markers (TTR, ZO-1). This minimal workflow enables rapid production of ChP-like organoids that recapitulate ChP morphology and marker expression, providing a potential platform for studies of cerebrospinal fluid physiology, barrier modelling, and translational neuroscience.
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α-Synuclein Pathology Spreads in a Midbrain-Hindbrain Assembloid Model.
Understanding the progression of α-synuclein pathology in neurodegenerative diseases such as Parkinson's disease (PD) is a longstanding challenge. Here, a novel midbrain-hindbrain-assembloid model that recapitulates the spread of α-synuclein pathology observed in PD patients, akin to Braak's hypothesis, is presented. Initially, the presence α-synuclein pathology is demonstrated in the hindbrain organoids. Subsequently, sophisticated tissue engineering methods are employed to create midbrain-hindbrain assembloids. These assembloids allow investigation and description of the spreading of α-synuclein pathology, as it progresses from the hindbrain components to the midbrain regions within the integrated structure. It is observed that an increase in α-synuclein in the hindbrain can induce transfer of the pathology into the healthy midbrain, as well as cause changes at the synapse level. The presented model constitutes a robust in vitro platform for investigating the mechanisms underlying α-synuclein spreading and disease progression, and holding potential for the screening of prospective therapeutics targeting the pathological propagation in PD and related synucleinopathies.
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Integrative single-cell RNA-seq analysis of vascularized cerebral organoids.
BACKGROUND: Cerebral organoids are three-dimensional in vitro cultured brains that mimic the function and structure of the human brain. One of the major challenges for cerebral organoids is the lack of functional vasculature. Without perfusable vessels, oxygen and nutrient supplies may be insufficient for long-term culture, hindering the investigation of the neurovascular interactions. Recently, several strategies for the vascularization of human cerebral organoids have been reported. However, the generalizable trends and variability among different strategies are unclear due to the lack of a comprehensive characterization and comparison of these vascularization strategies. In this study, we aimed to explore the effect of different vascularization strategies on the nervous system and vasculature in human cerebral organoids. RESULTS: We integrated single-cell RNA sequencing data of multiple vascularized and vascular organoids and fetal brains from publicly available datasets and assessed the protocol-dependent and culture-day-dependent effects on the cell composition and transcriptomic profiles in neuronal and vascular cells. We revealed the similarities and uniqueness of multiple vascularization strategies and demonstrated the transcriptomic effects of vascular induction on neuronal and mesodermal-like cell populations. Moreover, our data suggested that the interaction between neurons and mesodermal-like cell populations is important for the cerebrovascular-specific profile of endothelial-like cells. CONCLUSIONS: This study highlights the current challenges to vascularization strategies in human cerebral organoids and offers a benchmark for the future fabrication of vascularized organoids.