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Development of a 3-D Organoid System Using Human Induced Pluripotent Stem Cells to Model Idiopathic Autism

  • Jason W. Lunden
  • Madel Durens
  • Jonathan Nestor
  • Robert F. Niescier
  • Kevin Herold
  • Cheryl Brandenburg
  • Yu-Chih Lin
  • Gene J. Blatt
  • Michael W. NestorEmail author
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 25)

Abstract

Autism spectrum condition (ASC) is a complex set of behavioral and neurological responses reflecting a likely interaction between autism susceptibility genes and the environment. Autism represents a spectrum in which heterogeneous genetic backgrounds are expressed with similar heterogeneity in the affected domains of communication, social interaction, and behavior. The impact of gene-environment interactions may also account for differences in underlying neurology and wide variation in observed behaviors. For these reasons, it has been difficult for geneticists and neuroscientists to build adequate systems to model the complex neurobiology causes of autism. In addition, the development of therapeutics for individuals with autism has been painstakingly slow, with most treatment options reduced to repurposed medications developed for other neurological diseases. Adequately developing therapeutics that are sensitive to the genetic and neurobiological diversity of individuals with autism necessitates personalized models of ASC that can capture some common pathways that reflect the neurophysiological and genetic backgrounds of varying individuals. Testing cohorts of individuals with and without autism for these potentially convergent pathways on a scalable platform for therapeutic development requires large numbers of samples from a diverse population. To date, human induced pluripotent stem cells (iPSCs) represent one of the best systems for conducting these types of assays in a clinically relevant and scalable way. The discovery of the four Yamanaka transcription factors (OCT3/4, SOX2, c-Myc, and KLF4) [1] allows for the induction of iPSCs from fibroblasts [2], peripheral blood mononuclear cells (PBMCs, i.e. lymphocytes and monocytes) [3, 4], or dental pulp cells [5] that retain the original genetics of the individual from which they were derived [6], making iPSCs a powerful tool to model neurophysiological conditions. iPSCs are a readily renewable cell type that can be developed on a small scale for boutique-style proof-of-principle phenotypic studies and scaled to an industrial level for drug screening and other high-content assays. This flexibility, along with the ability to represent the true genetic diversity of autism, underscores the importance of using iPSCs to model neurophysiological aspects of ASC.

Keywords

Phenotypic screening Brain organoid Multielectrode array Live-cell calcium imaging High-throughput imaging 

Notes

Acknowledgements

We would like to thank Dr. Rania Deranieh and Omotayo Oduwole for technical assistance. We also like to thank Dr. John Hussman and Elizabeth Benevides for comments and reviews of this manuscript.

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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Jason W. Lunden
    • 1
  • Madel Durens
    • 1
  • Jonathan Nestor
    • 1
  • Robert F. Niescier
    • 1
  • Kevin Herold
    • 2
  • Cheryl Brandenburg
    • 1
  • Yu-Chih Lin
    • 1
  • Gene J. Blatt
    • 1
  • Michael W. Nestor
    • 1
    Email author
  1. 1.Program in NeuroscienceHussman Institute for AutismBaltimoreUSA
  2. 2.Program in Molecular MedicineUniversity of Maryland, School of MedicineBaltimoreUSA

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