Three-dimensional brain-on-chip model using human iPSC-derived GABAergic neurons and astrocytes: Butyrylcholinesterase post-treatment for acute malathion exposure

Liu, Lumei; Koo, Youngmi; Russell, Teal; Li, Yan; Yun, Yeoheung

doi:10.1371/journal.pone.0230335

Cited by 31 publications

(21 citation statements)

References 43 publications

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“…This increase also suggests that either CPF, its toxic metabolites, or other soluble factors were able to cross the BBB and interact directly with the neurons. In future experiments, recently published protocols describing cholinergic neuron differentiation from human-induced pluripotent stem cells (hiPSCs) can be implemented and integrated with this platform so that these results can be compared with those of human cholinergic neurons (McCracken et al, 2014;Paşca et al, 2015;Amin et al, 2016;Moreno et al, 2018;Pas, 2018;Liu et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier

Miller

McClain

Dodds

et al. 2021

Front. Bioeng. Biotechnol.

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Despite the significant progress in both scientific understanding and regulations, the safety of agricultural pesticides continues to be called into question. The need for complementary analytics to identify dysregulation events associated with chemical exposure and leverage this information to predict biological responses remains. Here, we present a platform that combines a model organ-on-chip neurovascular unit (NVU) with targeted mass spectrometry (MS) and electrochemical analysis to assess the impact of organophosphate (OP) exposure on blood-brain barrier (BBB) function. Using the NVU to simulate exposure, an escalating dose of the organophosphate chlorpyrifos (CPF) was administered. With up to 10 μM, neither CPF nor its metabolites were detected across the BBB (limit of quantitation 0.1 µM). At 30 µM CPF and above, targeted MS detected the main urinary metabolite, trichloropyridinol (TCP), across the BBB (0.025 µM) and no other metabolites. In the vascular chamber where CPF was directly applied, two primary metabolites of CPF, TCP and diethylthiophosphate (DETP), were both detected (0.1–5.7 µM). In a second experiment, a constant dose of 10 µM CPF was administered to the NVU, and though neither CPF nor its metabolites were detected across the BBB after 24 h, electrochemical analysis detected increases in acetylcholine levels on both sides of the BBB (up to 24.8 ± 3.4 µM) and these levels remained high over the course of treatment. In the vascular chamber where CPF was directly applied, only TCP was detected (ranging from 0.06 μM at 2 h to 0.19 μM at 24 h). These results provide chemical evidence of the substantial disruption induced by this widely used commercial pesticide. This work reinforces previously observed OP metabolism and mechanisms of impact, validates the use of the NVU for OP toxicology testing, and provides a model platform for analyzing these organotypic systems.

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Section: Resultsmentioning

confidence: 99%

Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier

Miller

McClain

Dodds

et al. 2021

Front. Bioeng. Biotechnol.

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“…The limitation makes iPSC-derived neurons difficult to analyze in unified experimental conditions. Nonetheless, iPSC-derived neurons have been widely used in designing a 3D brain-on-a-chip models [ 34 , 35 , 36 , 37 ], neurotoxicity testing [ 38 ], and disease modeling [ 39 , 40 ], owing to its advantages for various cellular populations and genetic conditions ( Figure 2 ). These models are expected to be used to develop personalized medicines (notably, for sporadic ND patients).…”

Section: Neural Cells For Neural Microphysiological System (Neuralmentioning

confidence: 99%

“… ( A ) Neurodegenerative disease modeling with various neuron cell sources; ( B ) Human induced pluripotent stem cell (iPSc)-derived neuron based neurodegenerative disease models. Reproduced with permission from Creative Commons Attribution [ 34 ]. …”

Section: Figurementioning

confidence: 99%

Microphysiological Systems for Neurodegenerative Diseases in Central Nervous System

Bae

Jang

et al. 2020

Micromachines

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Neurodegenerative diseases are among the most severe problems in aging societies. Various conventional experimental models, including 2D and animal models, have been used to investigate the pathogenesis of (and therapeutic mechanisms for) neurodegenerative diseases. However, the physiological gap between humans and the current models remains a hurdle to determining the complexity of an irreversible dysfunction in a neurodegenerative disease. Therefore, preclinical research requires advanced experimental models, i.e., those more physiologically relevant to the native nervous system, to bridge the gap between preclinical stages and patients. The neural microphysiological system (neural MPS) has emerged as an approach to summarizing the anatomical, biochemical, and pathological physiology of the nervous system for investigation of neurodegenerative diseases. This review introduces the components (such as cells and materials) and fabrication methods for designing a neural MPS. Moreover, the review discusses future perspectives for improving the physiological relevance to native neural systems.

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“…The utility of iPSC neurons stems mainly from their ability to recapitulateat the cellular levelspecific aspects of human neurodevelopment and neurodegenerative/neurological dysfunction previously only detected in patient-derived samples and/or non-human models. Hence, iPSC-derived neuron models, including organoids, "brain on a chip", neurospheres, and various two/three dimensional systems are forming key components of neurophysiologically relevant systems to understand, for example, neurite outgrowth and neural network function [24][25][26][27] . Similarly, the diverse steps of neurogenesis (i.e., neuronal progenitor cell (NPC) proliferation, migration and early differentiation of newly formed neurons) can be replicated by iPSC-derived neuron model systems 28 .…”

Section: Introductionmentioning

confidence: 99%

Extracellular cues accelerate neurogenesis of induced pluripotent stem cell derived neurons

Sharlow

Llaneza

Mendelson

et al. 2021

Preprint

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Neurogenesis is a complex process encompassing neuronal progenitor cell expansion/proliferation and differentiation, followed by neuron maturation. In vivo models are most commonly used to study neurogenesis; however, human induced pluripotent stem cell-derived (iPSC) neurons are increasingly used to establish cellular models of human neurological processes. Unfortunately, the differentiation and maturation of iPSC-derived neurons varies in methodology, is asynchronous, and has restricted experimental utility because of extended differentiation/maturation times. To accelerate and standardize iPS neuronal maturation, we differentiated and matured feeder layer-free iPSC-derived neuronal cultures under physiological oxygen levels (5%), and modified the underlying extracellular matrix and medium composition. Our results demonstrate that calretinin gene expression occurred earlier under our optimized iPS conditions and the corresponding neurogenesis burst associated with proliferative expansion occurred more synchronously, reliably emerging two and three weeks after differentiation. As expected, the expression of mature neuronal markers (i.e., NeuN+/Calbindin+) started at 4-weeks post-differentiation. qPCR microarray, western blot and single cell analyses using high content imaging indicated that 4-week iPS neuronal cultures were non-cycling with decreased expression of cyclin D1 and Ki67. Our data demonstrate that extracellular cues influence the kinetics of neurogenesis models and that feeder layer-free iPSC-derived neurogenesis can be reproducibly miniaturized.

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Three-dimensional brain-on-chip model using human iPSC-derived GABAergic neurons and astrocytes: Butyrylcholinesterase post-treatment for acute malathion exposure

Cited by 31 publications

References 43 publications

Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier

Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier

Microphysiological Systems for Neurodegenerative Diseases in Central Nervous System

Extracellular cues accelerate neurogenesis of induced pluripotent stem cell derived neurons

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