Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets

Abstract

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interactions as well as the presentation of restrictive and repetitive behaviors. ASD is highly heritable but genetically heterogenous with both common and rare genetic variants collaborating to predispose individuals to the disorder. In this review, we synthesize recent efforts to develop human induced pluripotent stem cell (iPSC)-derived models of ASD-related phenotypes. We firstly address concerns regarding the relevance and validity of available neuronal iPSC-derived models. We then critically evaluate the robustness of various differentiation and cell culture protocols used for producing cell types of relevance to ASD. By exploring iPSC models of ASD reported thus far, we examine to what extent cellular and neuronal phenotypes with potential relevance to ASD can be linked to genetic variants found to underlie it. Lastly, we outline promising strategies by which iPSC technology can both enhance the power of genetic studies to identify ASD risk factors and nominate pathways that are disrupted across groups of ASD patients that might serve as common points for therapeutic intervention.

The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation

“…This intensified need for basic and clinical research can be partially met by the generation and use of new tissue specific transgenic animal models [18]. Very recently, neural cells and cerebral organoids derived from iPS have been isolated from TSC patient specimens and these cellular models could reproduce some neurological defects seen in TSC [8,19,20]. However, there is still a need for brain-specific in vitro TSC models which could be easily handled and are affordable for most research labs.…”

“…Other mouse models have required additional genetic events, such as loss of PTEN, which does not occur in TSC patients [6]. In addition, genetically engineered human cortical spheroid models and neural cell model of TSC from embryonic stem cell (ES) or induced pluripotent stem cells (iPS) with loss/mutation of TSC1/TSC2 have been generated [7,8]. However, their similarity to human TSC and SEGA is uncertain, and engraftment of such cell lines in immunodeficient mice has not been achieved, which is a hallmark of a tumor cell line.…”

Harnessing the Power of Stem Cell Models to Study Shared Genetic Variants in Congenital Heart Diseases and Neurodevelopmental Disorders

“…For more directed assays, target gene expression via fluorescence reporters or cell-surface markers can be combined with flow cytometry to isolate populations that deviate from wild-type controls. Electrophysiological-or calcium-signaling assays will be able to pinpoint functional consequences in mutant neurons or cardiomyocytes [174,175]. Combining functional assays with mRNA sequencing such as Patch-seq [176] will directly link functional readouts with gene expression.…”

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders

“…In patients with sporadic forms, iPSCs represent a valuable method to investigate disease mechanisms in vitro. So far, studies have found phenotypes connected to calcium signaling, electrophysiology, cell proliferation, and synaptic density ( Pintacuda et al, 2021 ). Of note, among the many genes studied, various groups have focused on mutations of SHANK3 and SHANK2, structural proteins located at the postsynaptic density ( Chen et al, 2020 ; Lutz et al, 2020 ).…”