Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.

Background: Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia.

Methods: We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia.

Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder.

Unlabelled: We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters.

Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons.

Translational evidence suggests that cytokines involved in maternal immune activation (MIA), such as interleukin-6 (IL-6) and interferon-γ (IFN-γ), can cross the placenta, injure fetal brain, and predispose to neuropsychiatric disorders. To elaborate developmental neuronal sequelae of MIA, we differentiated human pluripotent stem cells to cortical neurons over a two-month period, exposing them to IL-6 or IFN-γ. IL-6 impacted expression of genes regulating extracellular matrix, actin cytoskeleton and TGF-β signaling while IFN-γ impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology.

Co-Culturing Microglia and Cortical Neurons Differentiated from Human Induced Pluripotent Stem Cells.

The ability to generate microglia from human induced pluripotent stem cells (iPSCs) provides new tools and avenues for investigating the role of microglia in health and disease. Furthermore, iPSC-derived microglia can be maintained in co-culture with iPSC-derived cortical neurons, which enable investigations of microglia-neuron interactions that are hypothesized to be dysregulated in a number of neuropsychiatric disorders. Human iPSCs were differentiated to generate microglia using an adapted version of a protocol developed by the Fossati group, and the iPSC-derived microglia were validated with marker analysis and real-time PCR.

Comparative Transcriptomic Analysis of Cerebral Organoids and Cortical Neuron Cultures Derived from Human Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (iPSCs) can be differentiated along various neuronal lineages to generate two-dimensional neuronal cultures as well as three-dimensional brain organoids. Such iPSC-derived cellular models are being utilized to study the basic biology of human neuronal function and to interrogate the molecular underpinnings of disease biology. The different cellular models generated from iPSCs have varying properties in terms of the diversity and organization of the cells as well as the cellular functions that are present.

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder.

Background: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds.

Methods: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids.

Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell-Derived Cerebral Organoids in Schizophrenia.

Importance: Three-dimensional cerebral organoids generated from patient-derived induced pluripotent stem cells (iPSCs) may be used to interrogate cellular-molecular underpinnings of schizophrenia.

Objective: To determine transcriptomic profiles and functional characteristics of cerebral organoids from patients with schizophrenia using gene expression studies, complemented with investigations of mitochondrial function through measurement of real-time oxygen consumption rate, and functional studies of neuronal firing with microelectrode arrays.

Design, Setting, And Participants: This case-control study was conducted at Massachusetts General Hospital between 2017 and 2019.

Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine.

Human postmortem studies suggest a major role for abnormalities in GABAergic interneurons in the prefrontal cortex in schizophrenia. Cortical interneurons differentiated from induced pluripotent stem cells (iPSCs) of schizophrenia subjects showed significantly lower levels of glutamate decarboxylase 67 (GAD67), replicating findings from multiple postmortem studies, as well as reduced levels of synaptic proteins gehpyrin and NLGN2. Co-cultures of the interneurons with excitatory cortical pyramidal neurons from schizophrenia iPSCs showed reduced synaptic puncta density and lower action potential frequency.

Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors.

Large cohorts of human induced pluripotent stem cells (iPSCs) from healthy donors are a potentially powerful tool for investigating the relationship between genetic variants and cellular behavior. Here, we integrate high content imaging of cell shape, proliferation, and other phenotypes with gene expression and DNA sequence datasets from over 100 human iPSC lines. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we extracted factors that captured the effects of intrinsic (genetic concordance between different cell lines from the same donor) and extrinsic (cell responses to different fibronectin concentrations) conditions.

Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs.

This corrects the article DOI: 10.1038/nature22403.

Modelling Autistic Neurons with Induced Pluripotent Stem Cells.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects more than 1% of children per current estimates. It has been characterised by the following two core behavioural phenotypes: (1) deficits in social interaction and communication and (2) repetitive behaviours, restricted interests and activities. Due to the complex nature of ASD, there are currently no effective treatments.

Common genetic variation drives molecular heterogeneity in human iPSCs.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative.

The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders.

Until now, models of psychiatric diseases have typically been animal models. Whether they were to be used to further understand the pathophysiology of the disorder, or as drug discovery tools, animal models have been the choice of preference in mimicking psychiatric disorders in an experimental setting. While there have been cellular models, they have generally been lacking in validity.