Using stem cell–derived neurons in drug screening for neurological diseases

Little, Daniel; Ketteler, Robin; Gissen, Paul; Devine, Michael J.

doi:10.1016/j.neurobiolaging.2019.02.008

Cited by 50 publications

(39 citation statements)

References 146 publications

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“…Stem cell-based models can also be used to screen drugs for treatment of neurodevelopmental disorders including ASD [91,104]. For example, one study screened 4421 unique compounds and identified 108 compounds that regulate neurite growth [105], a process which has been variably linked to some forms of ASD [106].…”

Section: Drug Discoverymentioning

confidence: 99%

Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled.Early development as a critical period for ASD susceptibility

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Section: Drug Discoverymentioning

confidence: 99%

Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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“…To investigate whether this is the case, human induced pluripotent stem cell (hiPSC)-derived neurons can be used. It is known that there is variability between different hiPSC-derived neuronal cell lines 54 . This could be the result of the generation protocol or the maturation stage in which the neurons were frozen.…”

Section: Effects Of Pfas On Rat Cortical Network Activitymentioning

confidence: 99%

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α1β2γ2L GABAA receptor and spontaneous neuronal network function in vitro

Tukker

Bouwman

Kleef

et al. 2020

Sci Rep

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Concerns about the neurotoxic potential of polyfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) increase, although their neurotoxic mechanisms of action remain debated. Considering the importance of the GABA A receptor in neuronal function, we investigated acute effects of PFAS on this receptor and on spontaneous neuronal network activity. PFOS (Lowest Observed Effect Concentration (LOEC) 0.1 µM) and PFOA (LOEC 1 µM) inhibited the GABA-evoked current and acted as non-competitive human GABA A receptor antagonists. Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM). However, exposure of networks of human induced pluripotent stem cell (hiPSC)-derived neurons decreased neuronal activity. The higher sensitivity of the α 1 β 2 γ 2L GABA A receptor for PFAS as compared to neuronal networks suggests that PFAS have additional mechanisms of action, or that compensatory mechanisms are at play. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. LOECs for PFAS on GABA A receptor and neuronal activity reported here are within or below the range found in blood levels of occupationally exposed humans. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are well-known perfluoroalkyl substances (PFAS) consisting of an eight-carbon chain in which hydrogen atoms have been substituted with fluorine. Their combined hydrophobic, hydrophilic, oleophobic and lipophobic properties make them ideal industrial surfactants for the manufacturing of consumer products, including paint, stain repellents, fire-fighting foams, and non-stick cookware coatings. The strong carbon-fluorine bond renders PFOS and PFOA highly persistent and studies have shown their presence in the environment, wildlife and even human blood (for reviews see 1,2). By 2002, production of PFOS was phased out and production phase out of PFOA followed in 2006 3. Recent studies indicate that these efforts may be responsible for a reduction in human blood levels in some areas, but the long half-lives of PFOS and PFOA result in slow elimination from environment and humans 4,5. Research has demonstrated that the (developing) nervous system is one of the most sensitive targets for PFOS and PFOA. In mice and rats exposed pre-and/or neonatally to PFOS or PFOA, increased motor activity, decreased habituation and deficits in spatial learning and memory abilities have been observed 6-11. Developmental neurotoxicity has also been observed in other species, including chicken 12 and zebrafish larvae 13,14. However, epidemiological studies have been inconclusive on the risks of PFAS exposure on neurodevelopment. Some studies indicate an association between prenatal PFOS and/or PFOA exposure and an increased risk on congenital cerebral palsy 15 , neuro-behavioural developmen...

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“…Stem cell technology, in particular human stem cells, has been transforming the fields of toxicology and pharmacology by providing noncancerous human‐specific cell models for research applications and detection of biologic activity of toxins and pharmaceuticals . While early studies were limited by controversies surrounding the use of embryonic stem cells, discoveries leading to the ability to efficiently re‐program adult human cells into human‐induced pluripotent stem cells (hiPSCs) have led to an explosion in progress in this field.…”

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confidence: 99%

Botulinum neurotoxins A, B, C, E, and F preferentially enter cultured human motor neurons compared to other cultured human neuronal populations

2019

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Human‐induced pluripotent stem cell (hiPSC)‐derived neurons can be exquisitely sensitive to botulinum neurotoxins (BoNTs), exceeding sensitivity of the traditionally used mouse bioassay. In this report, four defined hiPSC‐derived neuronal populations including primarily GABAergic, glutamatergic, dopaminergic, and motor neurons were examined for BoNT/A, B, C, D, E, and F sensitivity. The data indicate that sensitivity varies markedly for the BoNTs tested. Motor neurons are significantly more sensitive than other neuron types for all BoNTs except BoNT/D. Examination of SNARE protein levels and BoNT‐specific cell surface protein receptors reveals few differences between the cell types except greater expression levels of the receptor protein SV2C and synapsin‐IIa in motor neurons. This indicates that differential toxicity of BoNTs for motor neurons compared to other neuronal cell types involves multiple mechanisms.

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Using stem cell–derived neurons in drug screening for neurological diseases

Cited by 50 publications

References 146 publications

Human in vitro models for understanding mechanisms of autism spectrum disorder

Human in vitro models for understanding mechanisms of autism spectrum disorder

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α1β2γ2L GABAA receptor and spontaneous neuronal network function in vitro

Botulinum neurotoxins A, B, C, E, and F preferentially enter cultured human motor neurons compared to other cultured human neuronal populations

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