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Acrylamide exposure represses neuronal differentiation, induces cell apoptosis and promotes tau hyperphosphorylation in hESC-derived 3D cerebral organoids.
Acrylamide (ACR) is a common food contaminant with neurotoxic effects that are formed in the Maillard browning reaction during the heat processing of food. Importantly, pregnant women are also exposed to ACR in food during pregnancy and thus, the fetus is likely affected. However, the mechanisms of ACR-caused neurotoxicity on human brain development are still unclear. Many recent studies employed cerebral organoids based on human embryonic stem cells (hESC) for investigating human neurodevelopmental disorders and toxicity. Here, we generated hESC-derived cerebral organoids to evaluate the neurodevelopmental toxicity of ACR. The results indicated that exposure to ACR significantly altered the transcriptional profile, increased nuclear factor erythroid 2-related factor 2 (NRF2)-mediated gene expression, induced cell apoptosis, repressed neuronal differentiation, and promoted tau hyperphosphorylation in cerebral organoids, which may contribute to ACR-induced neurodevelopmental toxicity. These results indicate that the risk of transplacental exposure of the fetus to ACR should be evaluated and pregnant mothers should limit their exposure to ACR.
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Neutral competition explains the clonal composition of neural organoids.
Neural organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progenies arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This high variability exceeds what can be explained by existing stochastic models of corticogenesis and indicates the existence of an additional source of stochasticity. To explain this variability, we introduce the SAN model which distinguishes Symmetrically diving, Asymmetrically dividing, and Non-proliferating cells. In the SAN model, the additional source of stochasticity is the survival time of a lineage's pool of symmetrically dividing cells. These survival times result from neutral competition within the sub-population of all symmetrically dividing cells. We demonstrate that our model explains the experimentally observed variability of lineage sizes and derive the quantitative relationship between survival time and lineage size. We also show that our model implies the existence of a regulatory mechanism which keeps the size of the symmetrically dividing cell population constant. Our results provide quantitative insight into the clonal composition of neural organoids and how it arises. This is relevant for many applications of neural organoids, and similar processes may occur in other developing tissues both in vitro and in vivo.
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Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease.
The viscoelastic properties of tissues influence their morphology and cellular behavior, yet little is known about changes in these properties during brain malformations. Lissencephaly, a severe cortical malformation caused by LIS1 mutations, results in a smooth cortex. Here, we show that human-derived brain organoids with LIS1 mutation exhibit increased stiffness compared to controls at multiple developmental stages. This stiffening correlates with abnormal extracellular matrix (ECM) expression and organization, as well as elevated water content, measured by diffusion-weighted MRI. Short-term MMP9 treatment reduces both stiffness and water diffusion levels to control values. Additionally, a computational microstructure mechanical model predicts mechanical changes based on ECM organization. These findings suggest that LIS1 plays a critical role in ECM regulation during brain development and that its mutation leads to significant viscoelastic alterations.
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Vascular network-inspired diffusible scaffolds for engineering functional midbrain organoids.
Organoids, 3D organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present vascular network-inspired diffusible (VID) scaffolds to mimic physiological diffusion physics for generating functional organoids and phenotyping their drug response. Specifically, the VID scaffolds, 3D-printed meshed tubular channel networks, successfully engineer human midbrain organoids almost without necrosis and hypoxia in commonly used well plates. Compared with conventional organoids, these engineered organoids develop more physiologically relevant features and functions, including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared with conventional organoids with significant diffusion limits. This platform may provide insights for organoid development and therapeutic innovation.
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Endocrine-disrupting effects of environmental BPS and PFOS on human brain organoid development.
OBJECTIVE: Prenatal exposure to environmental endocrine-disrupting chemicals (EDCs) has been increasingly linked to neurodevelopmental impairment. Bisphenol S (BPS) and perfluoro-octane sulfonate (PFOS), two widely distributed EDCs detected in maternal and fetal tissues, raise concern due to their potential to interfere with brain development even at low environmental doses. METHODS: a phenotypic screening on human iPSC-derived cerebral organoids was performed to explore whether chronic exposure to BPS and PFOS could affect key neurodevelopmental processes. RESULTS: Both compounds affected key neurodevelopmental processes, including neuronal proliferation, cortical specification, synaptogenesis, glutamatergic differentiation, mitochondrial function, and choroid plexus formation. Importantly, TUNEL assay confirmed the absence of significant cytotoxicity. BPS exposure was associated with reduced ERβ, GPER, and phosphorylated Akt expression, suggesting a possible involvement of estrogen-related pathways. PFOS exposure coincided with decreased transthyretin expression, suggesting a potential influence on thyroid hormone availability. CONCLUSIONS: Exposure to multiple EDCs may disrupt distinct endocrine axes, producing cumulative impacts on human brain development. These findings underscore the value of human-relevant models for identifying endocrine-mediated neurodevelopmental hazards. While the observed molecular changes suggest distinct hormonal pathways may be involved, future mechanistic studies, including co-exposures with receptor modulators, will be required to establish causal relationships.
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A human iPSC-based perfusable and membrane-free neurovascular unit-on-chip connecting brain organoids to the blood-brain barrier.
The blood-brain barrier (BBB) protects the central nervous system by restricting entry of harmful blood-borne factors, but this selectivity actively limits delivery of therapeutics to the brain. Because BBB function is shaped by dynamic interactions within the neurovascular unit (NVU), particularly between brain endothelial cells, pericytes, and astrocytes, there is a need for human-relevant models that capture both barrier properties and neurovascular crosstalk in a controlled setting. Here, we present a novel human induced pluripotent stem cell (iPSC)-based NVU-on-chip that couples a perfusable, vessel-like BBB compartment to an adjacent open-top chamber housing a human brain organoid (hBO) via a membrane-free, hydrogel-based interface. This design enables co-culture of BBB and parenchymal components in close proximity while allowing direct cell-cell interactions at the barrier-tissue boundary without an artificial porous membrane. Using this platform, we demonstrate stable on-chip co-culture and show that hBO-derived astrocytes can sprout, migrate toward the BBB compartment and establish direct contact with endothelial cells, recapitulating the NVU structure. This system offers a human-specific framework for modeling NVU biology in health and disease and for evaluating BBB penetration together with downstream effects of candidate therapeutics on hBO.
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Multi-organ model assessment of neurotoxicity following exposure of liver spheroids to drugs.
Accurate prediction of drug toxicity is a major challenge for therapeutic development. The use of animal models for predicting toxicity has been a longstanding practice, but often falls short in accurately predicting human-specific responses. Human in vitro models, such as organoids and spheroids, provide alternative approaches to animal models. In this study, we employed primary human-derived liver spheroids (hLiSps) and human induced pluripotent stem cells (iPSC)-derived brain organoids (hiBOs) to create a combined Liver+Brain model for neurotoxicity assessment, to investigate the potential influence of incorporating a liver preconditioning component on toxic responses in the brain. Comparing the effect of six example drugs that are known to cause adverse clinical neurological effects, we observed that troglitazone (Trgl), tested at clinically relevant doses in the Liver+Brain model, caused a significantly greater reduction in cell viability compared to similar treatments in the Brain-only model. This was further confirmed across multiple donors and various stages of brain organoid development. In contrast, we found that high dose valproic acid treatment increased cell viability in the Liver+Brain model. Transcriptome analysis using RNA-seq revealed that liver-preconditioned Trgl elicited a more pronounced transcriptional response in hiBOs, identifying a 7-fold increase in the number of affected genes and over a 10-fold increase in affected pathways containing gene set components specifically associated with cell division and neurogenesis, which were not observed in the Brain model. Taken together, our data suggest that the addition of hLiSps to hiBOs is critical to accurately assess neurotoxicity using a comprehensive human in vitro model.
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The cytotoxicity of zinc oxide nanoparticles to 3D brain organoids results from excessive intracellular zinc ions and defective autophagy.
Although the neurotoxicity of ZnO nanoparticles (NPs) has been evaluated in animal and nerve cell culture models, these models cannot accurately mimic human brains. Three-dimensional (3D) brain organoids based on human-induced pluripotent stem cells have been developed to study the human brains, but this model has rarely been used to evaluate NP neurotoxicity. We used 3D brain organoids that express cortical layer proteins to investigate the mechanisms of ZnO NP-induced neurotoxicity. Cytotoxicity caused by high levels of ZnO NPs (64 μg/mL) correlated with high intracellular Zn ion levels but not superoxide levels. Exposure to a non-cytotoxic concentration of ZnO NPs (16 μg/mL) increased the autophagy-marker proteins LC3B-II/I but decreased p62 accumulation, whereas a cytotoxic concentration of ZnO NPs (64 μg/mL) decreased LC3B-II/I proteins but did not affect p62 accumulation. Fluorescence micro-optical sectioning tomography revealed that 64 μg/mL ZnO NPs led to decreases in LC3B proteins that were more obvious at the outer layers of the organoids, which were directly exposed to the ZnO NPs. In addition to reducing LC3B proteins in the outer layers, ZnO NPs increased the number of micronuclei in the outer layers but not the inner layers (where LC3B proteins were still expressed). Adding the autophagy flux inhibitor bafilomycin A1 to ZnO NPs increased cytotoxicity and intracellular Zn ion levels, but adding the autophagy inducer rapamycin only slightly decreased cellular Zn ion levels. We conclude that high concentrations of ZnO NPs are cytotoxic to 3D brain organoids via defective autophagy and intracellular accumulation of Zn ions.
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Radiofrequency regulates the BET-mediated pathways in radial glia differentiation in human cortical development.
The human brain represents one of the most complex organs in our body, with development regulated by an intricate genetic program. Recently, non-genetic factors, such as prenatal stress, infection, and diet, have been shown to influence brain development. Radiofrequency radiation (RF; 800-2,400 MHz), emitted by natural and artificial sources such as microwaves and cell phones, represents a non-invasive environmental factor. Using human cortical organoids (hCOs) derived from human embryonic stem cells (hESCs), we investigate RF's effects on corticogenesis. We find that RF exposure regulates the differentiation of human and non-human primate radial glia progenitors, maintaining stem cell identity and delaying differentiation. Neurons differentiated under RF treatment show induction of expression of human endogenous retroviruses. Importantly, inhibitors for the BET (bromodomain and extraterminal) protein rescue RF-induced developmental defects in hCOs. Our findings reveal a mechanism by which RF modulates early brain development, offering a non-biological approach to regulate neural stem cell self-renewal.
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Targeting Human Endothelial Cells with Glutathione and Alanine Increases the Crossing of a Polypeptide Nanocarrier through a Blood-Brain Barrier Model and Entry to Human Brain Organoids.
Nanoparticles (NPs) are the focus of research efforts that aim to develop successful drug delivery systems for the brain. Polypeptide nanocarriers are versatile platforms and combine high functionality with good biocompatibility and biodegradability. The key to the efficient brain delivery of NPs is the specific targeting of cerebral endothelial cells that form the blood-brain barrier (BBB). We have previously discovered that the combination of two different ligands of BBB nutrient transporters, alanine and glutathione, increases the permeability of vesicular NPs across the BBB. Our aim here was to investigate whether the combination of these molecules can also promote the efficient transfer of 3-armed poly(l-glutamic acid) NPs across a human endothelial cell and brain pericyte BBB co-culture model. Alanine and glutathione dual-targeted polypeptide NPs showed good cytocompatibility and elevated cellular uptake in a time-dependent and active manner. Targeted NPs had a higher permeability across the BBB model and could subsequently enter midbrain-like organoids derived from healthy and Parkinson's disease patient-specific stem cells. These results indicate that poly(l-glutamic acid) NPs can be used as nanocarriers for nervous system application and that the right combination of molecules that target cerebral endothelial cells, in this case alanine and glutathione, can facilitate drug delivery to the brain.