A Human Brain Microphysiological System Derived from Induced Pluripotent Stem Cells to Study Neurological Diseases and Toxicity

July 16, 2018

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.

Animal models have poor predictivity for human health and do not always mimic human pathology, with more than 90% of all drugs failing in clinical trials, despite extensive animal testing. Therefore, BrainSim, a 3D in vitro iPSC-derived human 3D brain microphysiological system, comprised of mature neurons (glutamatergic, dopaminergic, and GABAergic neurons) and glial cells (astrocytes and oligodendrocytes) was developed. Human in vitro models that can capture the function of glial cells and allow the quantification of myelin are essential to drug discovery.

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