Abstract
BackgroundA variety of neurological disorders including neurodegenerative diseases and infection by neurotropic viruses can cause structural and functional changes in the central nervous system (CNS), resulting in long-term neurological sequelae. An improved understanding of the pathogenesis of these disorders is important for developing efficacious interventions. Human induced pluripotent stem cells (hiPSCs) offer an extraordinary window for modeling pathogen-CNS interactions, and other cellular interactions, in three-dimensional (3D) neuronal cultures that can recapitulate several aspects of in vivo brain tissue.MethodsHerein, we describe a prototype of scaffold-free hiPSC-based adherent 3D (A-3D) human neuronal cultures in 96-well plates. To test their suitability for drug screening, A-3D neuronal cultures were infected with herpes simplex virus type 1 (HSV-1) with or without acyclovir.ResultsThe half maximal inhibitory concentration (IC50) of acyclovir was 3.14 μM and 3.12 μM determined using flow cytometry and the CX7 High Content Screening platform, respectively.ConclusionsOur A-3D neuronal cultures provide an unprecedented opportunity for high-content drug screening programs to treat human CNS infections.
Highlights
A variety of neurological disorders including neurodegenerative diseases and infection by neurotropic viruses can cause structural and functional changes in the central nervous system (CNS), resulting in long-term neurological sequelae
We investigated the feasibility of generating adherent 3D (A-3D) neuronal cultures from human induced pluripotent stem cell (hiPSC) lines derived from two different individuals
Using herpes simplex virus type 1 (HSV-1) infection as an example, we further demonstrate the utility of A-3D cultures grown in 96-well plates for CNS antiviral drug screening
Summary
A variety of neurological disorders including neurodegenerative diseases and infection by neurotropic viruses can cause structural and functional changes in the central nervous system (CNS), resulting in long-term neurological sequelae. The experimental approaches to modeling central nervous system (CNS) disorders and infections have changed profoundly thanks to human induced pluripotent stem cell (hiPSC) technologies. It is possible to generate and manipulate nearly limitless numbers of hiPSC-derived neuronal lineage cells reprogrammed from specific individuals. Such an approach is essential to push the boundaries of personalized medicine since individuals show differences in susceptibility to common environmental, genetic, or infectious stressors. HiPSC-based models can be used to investigate the pathogenesis of neurotropic viruses and neuropsychiatric and neurodegenerative diseases at the cellular and molecular levels, modeling individual and cell-type specific differences in susceptibility to a given mutation, injury or pathogen, and as cellular platforms for drug screens.
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