How human cellular models have advanced basic and translational research in ASD is examined and key cellular and molecular convergent phenotypes that have emerged are identified.
Abstract
Human cellular models are enabling the in vitro study of the complex molecular and cellular mechanisms underlying autism spectrum disorder (ASD). Human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC)- derived models have progressed from investigating single genes to multiplexed approaches that have allowed the study of several ASD risk genes in parallel, which have expanded our understanding of how coding and noncoding genetic variants shape cellular and molecular phenotypes in ASD. Additionally, these models have identified several convergent pathogenic mechanisms in ASD, including dysregulated neurogenesis, altered cell type specification (such as defects in glutamatergic neurons and expansion of GABAergic neurons), and disrupted synaptic activity. Common molecular principles are also emerging, including dysregulation of chromatin, WNT signaling, and mTOR signaling. hiPSC models of ASD have also been used to evaluate the effect of several FDA-approved therapeutic compounds on early human neural development, such as mTOR inhibitors, some of which are currently in clinical trials for ASD-related conditions. Although human cellular models have limitations, their unique strength is the ability to reveal early developmental pathophysiology and the potential to correlate in vitro phenotypes with the clinical features of patient donors. Here, we examine how human cellular models have advanced basic and translational research in ASD and identify key cellular and molecular convergent phenotypes that have emerged.
Key links between peripheral protein dysregulation and neuronal function and behavior are revealed, offering new insights into systemic contributions to ASD pathophysiology and highlighting potential therapeutic targets for mitigating symptom severity.
Samia M. Ltaief, Safa Salim, Sadam Hussain et al.· Translational Psychiatry· 0 citations
Recent advances and ongoing challenges of human cortical organoid models of genetic and acquired epilepsies hold promise for advancing mechanistic understanding of epilepsy and enabling the development of more precise therapeutic strategies.
Miranda Walker, Jack M. Parent· Epilepsy Currents· 0 citations
RNA-sequencing, 3-dimensional protein-centric chromatin conformation, and whole genome DNA methylation sequencing approaches are used to investigate hippocampal tissue from an ASD mouse model to determine if multi-omic data integration improves the resolution of key molecular pathways contributing to the complex ASD phenotype.
Carolina D Alberca, Kwangmoon Park, L. Papale et al.· Molecular Psychiatry· 0 citations
The prevalence of autism spectrum disorder (ASD) has risen over the decades, reflecting improved awareness and evolving diagnostic practice. ASD is characterized by clinical and biological heterogeneity, with diverse genetic and environmental risk factors converging on disruption of synaptic function, circuits, and behaviour. This complexity limits mechanistic inference from human studies and underscores the importance of animal models for establishing causal relationships between risk mechanisms and ASD-relevant phenotypes. In this review, we outline the framework used to evaluate the relevance of animal models-construct, face, and predictive validity-and summarize the behavioural paradigms used to assess core ASD-related domains in rodents, including social interaction and communication, restricted and repetitive behaviours, and cognitive flexibility. We then examine mouse models of ASD, encompassing genetically engineered lines and inbred and idiopathic strains, discussing their mechanistic contributions, limitations, and sources of phenotypic variability. In addition, we briefly review environmental models and complementary animal species, which provide insights into distinct aspects of ASD biology. Collectively, the available models reveal convergent molecular and circuit mechanisms underlying ASD-related phenotypes. When interpreted within a framework and supported by standardized behavioural and physiological approaches, these models constitute a powerful platform for elucidating ASD pathophysiology and for guiding the preclinical development of targeted therapeutic strategies.
Pilar Martinez Olondo, A. de Kerchove d’Exaerde· Developmental Medicine & Chi...· 0 citations
In this manuscript, we report the development of a comprehensive resource designed to harness the transformative potential of patient-derived induced pluripotent stem cells (iPSCs) to advance the study of neurodevelopmental disorders (NDDs). Using CRISPR-Cas-mediated genome editing, the Human Neuron Core generated a repository comprising 29 isogenic iPSC pairs, two sex-matched parental control iPSC pairs, and one unmatched patient line representing six monogenic NDDs: Tuberous Sclerosis Complex, PTEN Hamartoma Tumor Syndrome, KCNQ2 Developmental and Epileptic Encephalopathy, FOXG1 Syndrome, Phelan-McDermid Syndrome, and SETBP1 Haploinsufficiency Disorder. In parallel, detailed clinical phenotyping data were collected to enable comparison of cellular phenotypes with clinical severity in future studies. This integrated collection of genetically defined iPSC lines and associated clinical data provides a powerful platform for investigating disease mechanisms and advancing iPSC-based drug discovery for NDDs.
Cidi Chen, Wardiya Afshar-Saber, I. Iglesias et al.· Stem Cell Research· 0 citations
Mounting evidence implicates dysregulation of the neuroimmune system in Alzheimer’s disease (AD). Neuroimmune cells, namely microglia and astrocytes, have the potential to contribute to AD through mechanisms such as promoting neuroinflammation and propagating amyloid-β (Aβ) and tau aggregates. Human induced pluripotent stem cell (hiPSC)-derived models offer advantages for studying the AD neuroimmune system, such as recapitulating genetic variants associated with the disease and allowing for precise manipulation of human cells in vitro. Here, we provide an overview of modern techniques for generating 2-dimensional (2D) monocultures and co-cultures, 3-dimensional (3D) organoids and assembloids, and chimeras containing hiPSC-derived microglia and astrocytes. Then, we highlight recent studies that have utilized hiPSC-derived neuroimmune models to investigate AD risk variants in genes encoding apolipoprotein E (APOE) and triggering receptor on myeloid cells 2 (TREM2), mutations known to cause familial AD in genes encoding presenilin 1 (PSEN1) and 2 (PSEN2) and amyloid precursor protein (APP), and trisomy 21 leading to Down syndrome-associated AD (DS-AD). We then briefly summarize recent studies that have utilized hiPSC-derived neuroimmune models lacking disease-associated variants to study the clearance of Aβ and tau aggregates. Finally, we discuss notable limitations of these models and reflect on future directions for this area of research, including the use of cultures with increasing cellular diversity and structural complexity, advancements in live-imaging techniques for detecting AD pathology in vitro, and drug screening.
Rose Summers, Daphne Quang, Noah R. Johnson· International Journal of Mol...· 0 citations