Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies

Abstract

Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. Autism Res 2016, 9: 513-535. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Cortical interneuron function in autism spectrum condition

“…Although the iPSC field is in early development, the potential to model aspects of ASC using human neurons is promising. 128 The ability to develop human cortical tissue in vitro presents scientists with multiple new options to design experiments that integrate results from both rodent and clinical studies that will result in greater clinical translatability.…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…Indeed, brain imaging studies from individuals with ASD and anatomical measurements of neuronal structure in post-mortem tissues exhibit differences in neuronal connectivity derived from the disruption of neurite outgrowth, synapse formation and stabilization (Raymond et al, 1996; Hutsler and Zhang, 2010; Penzes et al, 2011). Studies of human induced pluripotent stem cells (iPSCs) derived from people with ASD also have identified defects of neuronal structure (Habela et al, 2015; Nestor et al, 2015). Genome-wide association studies on individuals with ASD and their families revealed several risk genes that may be the common molecular targets in autism (Bucan et al, 2009; Glessner et al, 2009; Hussman et al, 2011; O’Roak et al, 2011, 2012a; Buxbaum et al, 2012, 2014; Sanders et al, 2012; Shi et al, 2013; Stamou et al, 2013; Yu et al, 2013; An et al, 2014; Brett et al, 2014; Cukier et al, 2014; De Rubeis et al, 2014; Iossifov et al, 2014; McGee et al, 2014; Pinto et al, 2014; Ronemus et al, 2014; Toma et al, 2014; Yuen et al, 2015).…”

Utilization Avenues for Induced Pluripotent Stem Cells in Autism

“…Thus, iPSC models not only enable the examination of molecular interactions and the fate of cells, but also provide the possibility to make investigations within the context of more complex systems and biochemical processes 17 . Due to the electrophysiological, gene expression, and other cell-based quantitative studies that can be performed on iPSC models, efforts to develop comprehensive models for autism, which have so far been slow in progress, can gain momentum 18 .…”