title: A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity.
abstract: Human in vitro models of brain neurophysiology are needed to investigate molecular and cellular mechanisms associated with neurological disorders and neurotoxicity. We have developed a reproducible iPSC-derived human 3D brain microphysiological system (BMPS), comprised of differentiated mature neurons and glial cells (astrocytes and oligodendrocytes) that reproduce neuronal-glial interactions and connectivity. BMPS mature over eight weeks and show the critical elements of neuronal function: synaptogenesis and neuron-to-neuron (e.g., spontaneous electric field potentials) and neuronal-glial interactions (e.g., myelination), which mimic the microenvironment of the central nervous system, rarely seen in vitro before. The BMPS shows 40% overall myelination after 8 weeks of differentiation. Myelin was observed by immunohistochemistry and confirmed by confocal microscopy 3D reconstruction and electron microscopy. These findings are of particular relevance since myelin is crucial for proper neuronal function and development. The ability to assess oligodendroglial function and mechanisms associated with myelination in this BMPS model provide an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating diseases. The BMPS provides a suitable and reliable model to investigate neuron-neuroglia function as well as pathogenic mechanisms in neurotoxicology.
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pamies
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Division of Neuroimmunology, Johns Hopkins University, Baltimore, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Barreras
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Block
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Institute for Cell Engineering, Johns Hopkins University, Baltimore, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Makri
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Division of Neuroimmunology, Johns Hopkins University, Baltimore, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.
authors.forename: Daphne
authors.initials: D
authors.lastname: Wiersma
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.
authors.forename: Lenna
authors.initials: L
authors.lastname: Smirnova
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Institute for Cell Engineering, Johns Hopkins University, Baltimore, USA.
authors.forename: Ce
authors.initials: C
authors.lastname: Zang
authors.affiliation: Hugo Moser Institute at the Kennedy Krieger, Johns Hopkins University, Baltimore, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bressler
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Institute for Cell Engineering, Johns Hopkins University, Baltimore, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Christian
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: Harris
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Institute for Cell Engineering, Johns Hopkins University, Baltimore, USA.|The Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, USA.
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Ming
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, USA.
authors.forename: Cindy J
authors.initials: CJ
authors.lastname: Berlinicke
authors.affiliation: US Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kyro
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Institute for Cell Engineering, Johns Hopkins University, Baltimore, USA.|The Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, USA.|Division of Neuroimmunology, Johns Hopkins University, Baltimore, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Pardo
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.|University of Konstanz, Konstanz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.affiliation: Center for Alternatives to Animal Testing, Johns Hopkins University, Baltimore, USA.
authors.forename: Helena T
authors.initials: HT
authors.lastname: Hogberg
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001921:Brain; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D009186:Myelin Sheath; D009836:Oligodendroglia / Q000166:cytology
keywords: 3D culture; CNS; brain; microphysiological system; myelination