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Proteome signatures of joint toxicity to arsenic (As) and lead (Pb) in human brain organoids with optic vesicles.
Arsenic (As) and lead (Pb) are toxins found in the natural surroundings, and the harmful health outcomes caused by the co-exposure of such toxins have become a considerable problem. However, the joint neurotoxicity of As and Pb to neurodevelopment and the underlying mechanisms remain unclear. Pluripotent stem cell-derived human brain organoids are emerging animal model alternatives for understanding neurological-related diseases. Therefore, we utilized brain organoids with optic vesicles (OVB-organoids) to systematically analyze the neurotoxicity of As and Pb. After 24 h of As and/or Pb exposure, hematoxylin-eosin staining revealed that As and Pb exposure could cause disorders in the structure of the ventricular zone and general cell disarrangement in OVB-organoids. Immunostaining displayed that OVB-organoids are more susceptible to As and Pb co-exposure than independent exposure in apoptosis, proliferation, and cell differentiation. Meanwhile, even though As and Pb could both hinder cell proliferation, contrary to Pb, As could induce an increasing proportion of mitotic (G2/M) cells. The proteome landscape of OVB-organoids illustrated that Pb synergized with As in G2/M arrest and the common role of As and Pb in carcinogenesis. Besides, proteomics analyses suggested the consequential role of autophagy and Wnt pathway in the neurotoxicity of As and Pb co-exposure. Overall, our findings provide penetrating insights into the cell cycle, carcinogenesis, autophagy, and Wnt pathway underlying the As and Pb binary exposure scenarios, which could enhance our understanding of the mixture neurotoxicity mechanisms.
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The ADCY1-mediated cAMP signaling pathway mediates functional effects of montelukast treatment in brain organoids.
Montelukast (MTK) is a drug widely used for treating allergic rhinitis and asthma. However, severe neuropsychiatric adverse events related to MTK have been reported, with limited understanding of the underlying mechanisms. Here we leveraged human forebrain organoids (hFOs) and showed that MTK exposure in hFOs downregulated the expression of genes associated with multiple neuronal functions and neuropsychiatric disorders. The following integrative analysis highlighted adenylate cyclase 1 (ADCY1), a main regulator of the cAMP signaling pathway, as a hub gene mediating the functional effects of MTK exposure. We also showed that MTK exposure resulted in a reduction of cAMP and neuroactivities, and caused neural maturation defects. These cellular phenotypes could be recapitulated by treating hFOs with ST034307, a selective ADCY1 inhibitor, or partially rescued by ADCY1 overexpression in hFOs. Together, this study underscored that MTK exposure caused neuropsychiatric effects through inhibiting the ADCY1-mediated cAMP signaling pathway.
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Choroid Plexus Organoids: Harnessing CSF Gatekeepers for Brain Therapeutics.
Barrier properties of the choroid plexus (ChP) help protect the brain from the external world. In Science, Pellegrini et al. (2020) report the successful creation of human ChP organoids, which produce a cerebrospinal fluid-like secretion and recapitulate barrier functions, thereby inspiring new advances for targeted brain therapeutics.
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Thymosin beta 4 as an Alzheimer disease intervention target identified using human brain organoids.
The developmental origin of Alzheimer disease (AD) has been proposed but is arguably debated. Here, we developed cerebral organoids from induced pluripotent stem cells (iPSCs) with mutations in amyloid precursor protein (APP) associated with familial AD (fAD) and analyzed the dynamic changes of cellular states. We found that mature neurons induced in fAD organoids markedly decreased compared to that of health control, accompanied with increased cell senescence and β-amyloid (Aβ) production. Interestingly, the expression level of the gene TMSB4X that encodes thymosin beta 4 (Tβ4) significantly decreased both in fAD organoids' neurons and AD patients' excitatory neurons. Remarkably, the neurodevelopmental deficits and Aβ formation in fAD organoids were rescued by treatment with Tβ4. The beneficial effects of Tβ4 were also revealed in 5xfAD model mice. Thus, this study has identified Tβ4 as a neuroprotective factor that may mitigate altered neurogenesis and AD pathology, highlighting a potential for disease intervention.
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Patterning ganglionic eminences in developing human brain organoids using a morphogen-gradient-inducing device.
In early neurodevelopment, the central nervous system is established through the coordination of various neural organizers directing tissue patterning and cell differentiation. Better recapitulation of morphogen gradient production and signaling will be crucial for establishing improved developmental models of the brain in vitro. Here, we developed a method by assembling polydimethylsiloxane devices capable of generating a sustained chemical gradient to produce patterned brain organoids, which we termed morphogen-gradient-induced brain organoids (MIBOs). At 3.5 weeks, MIBOs replicated dorsal-ventral patterning observed in the ganglionic eminences (GE). Analysis of mature MIBOs through single-cell RNA sequencing revealed distinct dorsal GE-derived CALB2+ interneurons, medium spiny neurons, and medial GE-derived cell types. Finally, we demonstrate long-term culturing capabilities with MIBOs maintaining stable neural activity in cultures grown up to 5.5 months. MIBOs demonstrate a versatile approach for generating spatially patterned brain organoids for embryonic development and disease modeling.
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Synergistic neurotoxicity of mono-butyl phthalate and bisphenol A at environmentally relevant concentrations: Multi-Omics evidence for ferroptosis via glutathione metabolism disruption in neural stem cells and brain organoids.
Evaluating endocrine-disrupting chemicals (EDCs) risk such as mono-butyl phthalate (MBP) and bisphenol A (BPA) raises a pressing question: can doses deemed safe for each individual exposure become hazardous in combination? This study aimed to determine whether environmentally relevant concentrations of MBP and BPA exert synergistic neurotoxicity and to elucidate the underlying molecular mechanisms using an integrated multi-omics approach. Exposure concentrations (20 nM each) were derived from epidemiological biomonitoring data. Primary neural stem cells (NSCs) were used to detect CCK-8, reactive oxygen species (ROS), and apoptosis Synergy was evaluated using the Bliss independence model and two-way ANOVA. Transcriptomic (RNA-seq) and untargeted metabolomic (LC-MS) profiling were performed, followed by integrative pathway analysis. Three-dimensional (3D) brain organoids were used to validate the main findings. Co-exposure to MBP and BPA at equimolar concentrations synergistically reduced cell proliferation (BlissΔ >0, E_Observed = 0.371 vs. E_Bliss = 0.163) and synergistically elevated intracellular ROS (interaction index = 2.21, p = 0.0066; two-way ANOVA interaction p = 0.033). Transcriptomic and metabolomic analyses converged on glutathione metabolism as the most significantly dysregulated pathway in the co-exposure group. Integrated multi-omics analysis revealed ferroptosis may serve as the primary mode of synergistic cell death. Three-dimensional brain organoids confirmed the ferroptosis signature, with significantly decreased GPX4 and SLC7A11 protein expression and concomitantly increased ACSL4 in the co-exposure group. In summary, MBP and BPA co-exposure at human-relevant doses synergistically induces neurotoxicity in NSCs through glutathione metabolism disruption and subsequent ferroptosis. These findings underscore the importance of evaluating chemical mixtures rather than individual compounds in neurodevelopmental risk assessment.
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Cerebral organoids display dynamic clonal growth and tunable tissue replenishment.
During brain development, neural progenitors expand through symmetric divisions before giving rise to differentiating cell types via asymmetric divisions. Transition between those modes varies among individual neural stem cells, resulting in clones of different sizes. Imaging-based lineage tracing allows for lineage analysis at high cellular resolution but systematic approaches to analyse clonal behaviour of entire tissues are currently lacking. Here we implement whole-tissue lineage tracing by genomic DNA barcoding in 3D human cerebral organoids, to show that individual stem cell clones produce progeny on a vastly variable scale. By using stochastic modelling we find that variable lineage sizes arise because a subpopulation of lineages retains symmetrically dividing cells. We show that lineage sizes can adjust to tissue demands after growth perturbation via chemical ablation or genetic restriction of a subset of cells in chimeric organoids. Our data suggest that adaptive plasticity of stem cell populations ensures robustness of development in human brain organoids.
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SARS-CoV2 infection triggers inflammatory conditions and astrogliosis-related gene expression in long-term human cortical organoids.
SARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use long-term human stem cell-derived cortical organoids to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection of astrocytes, deep projection neurons, upper callosal neurons, and inhibitory neurons in 6 months of human cortical organoids. Interestingly, astrocytes showed the highest infection rate among all infected cell populations which led to changes in their morphology and upregulation of SERPINA3, CD44, and S100A10 astrogliosis markers. Further, transcriptomic analysis revealed overall changes in expression of genes related to cell metabolism, astrogliosis and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and lead to the resilience of dysregulated neurons and astrocytes within an inflammatory environment.
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Resolution of insoluble proteins in rat brain subcellular fractions.
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Self-Organized Nanostructure Modified Microelectrode for Sensitive Electrochemical Glutamate Detection in Stem Cells-Derived Brain Organoids.
Neurons release neurotransmitters such as glutamate to communicate with each other and to coordinate brain functioning. As increased glutamate release is indicative of neuronal maturation and activity, a system that can measure glutamate levels over time within the same tissue and/or culture system is highly advantageous for neurodevelopmental investigation. To address such challenges, we develop for the first time a convenient method to realize functionalized borosilicate glass capillaries with nanostructured texture as an electrochemical biosensor to detect glutamate release from cerebral organoids generated from human embryonic stem cells (hESC) that mimic various brain regions. The biosensor shows a clear catalytic activity toward the oxidation of glutamate with a sensitivity of 93 ± 9.5 nA·µM-1·cm-2. It was found that the enzyme-modified microelectrodes can detect glutamate in a wide linear range from 5 µM to 0.5 mM with a limit of detection (LOD) down to 5.6 ± 0.2 µM. Measurements were performed within the organoids at different time points and consistent results were obtained. This data demonstrates the reliability of the biosensor as well as its usefulness in measuring glutamate levels across time within the same culture system.