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Related Concept Videos

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Related Experiment Video

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Human IPSC-Derived Model to Study Myelin Disruption.

Megan Chesnut1, Hélène Paschoud2, Cendrine Repond2

  • 1Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD 21205, USA.

International Journal of Molecular Sciences
|September 10, 2021
PubMed
Summary

This study introduces a human 3D brain organoid model for studying myelin development and disruption. The model effectively identifies chemicals that cause neurotoxicity by disrupting myelin, offering a valuable tool for disease research.

Keywords:
developmental diseasesdevelopmental neurotoxicitymyelinneurotoxicityoligodendrocytesorganoidorganotypic

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Toxicology

Background:

  • Myelin is crucial for central nervous system function, and its disruption is linked to neurodevelopmental and neurodegenerative diseases.
  • Existing animal models inadequately represent human oligodendrocyte function, highlighting the need for human in vitro models.
  • Human induced pluripotent stem cell (iPSC)-derived 3D cultures offer a promising avenue for studying myelination in vitro.

Purpose of the Study:

  • To refine a human iPSC-derived 3D brain organoid model (BrainSpheres) for studying myelination and myelin disruption.
  • To establish and validate a methodology for quantifying chemical-induced myelin disruption.
  • To identify compounds that disrupt myelin and assess the model's relevance for neurotoxicity screening.

Main Methods:

  • Utilized human iPSC-derived 3D brain organoids (BrainSpheres) containing myelinated axons.
  • Quantified myelination using immunostaining/confocal microscopy (myelin basic protein, neurofilament proteins, proteolipid protein 1) and Western blot for PLP1.
  • Evaluated the effects of known myelin disruptors (cuprizone, Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, methyl mercury) and a negative control (ibuprofen).

Main Results:

  • The BrainSphere model demonstrated reproducible myelination.
  • Cuprizone, Bisphenol A, and Tris(1,3-dichloro-2-propyl) phosphate significantly decreased myelination.
  • Methyl mercury did not affect myelination, while ibuprofen served as a negative control with no observed effect.

Conclusions:

  • The developed methodology allows for the quantification of myelin disruption in a human 3D organoid model.
  • The BrainSphere model is relevant for studying myelination/demyelination processes and for identifying chemical-induced myelin disruptors.
  • This model provides a valuable platform for developmental neurotoxicity testing and understanding myelin-related diseases.