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Human Oligodendrocytes and Myelin In Vitro to Evaluate Developmental Neurotoxicity
Article

Human IPSC-Derived Model to Study Myelin Disruption

1
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD 21205, USA
2
Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland
3
Center for Alternative to Animla Testing Europe, University of Konstanz, 78464 Konstanz, Germany
4
Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland
*
Authors to whom correspondence should be addressed.
Academic Editor: Irmgard Tegeder
Int. J. Mol. Sci. 2021, 22(17), 9473; https://doi.org/10.3390/ijms22179473
Received: 29 July 2021 / Revised: 27 August 2021 / Accepted: 28 August 2021 / Published: 31 August 2021
Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption. View Full-Text
Keywords: developmental neurotoxicity; neurotoxicity; organotypic; organoid; myelin; developmental diseases; oligodendrocytes developmental neurotoxicity; neurotoxicity; organotypic; organoid; myelin; developmental diseases; oligodendrocytes
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MDPI and ACS Style

Chesnut, M.; Paschoud, H.; Repond, C.; Smirnova, L.; Hartung, T.; Zurich, M.-G.; Hogberg, H.T.; Pamies, D. Human IPSC-Derived Model to Study Myelin Disruption. Int. J. Mol. Sci. 2021, 22, 9473. https://doi.org/10.3390/ijms22179473

AMA Style

Chesnut M, Paschoud H, Repond C, Smirnova L, Hartung T, Zurich M-G, Hogberg HT, Pamies D. Human IPSC-Derived Model to Study Myelin Disruption. International Journal of Molecular Sciences. 2021; 22(17):9473. https://doi.org/10.3390/ijms22179473

Chicago/Turabian Style

Chesnut, Megan, Hélène Paschoud, Cendrine Repond, Lena Smirnova, Thomas Hartung, Marie-Gabrielle Zurich, Helena T. Hogberg, and David Pamies. 2021. "Human IPSC-Derived Model to Study Myelin Disruption" International Journal of Molecular Sciences 22, no. 17: 9473. https://doi.org/10.3390/ijms22179473

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