scholarly journals CNTN5−/+orEHMT2−/+iPSC-Derived Neurons from Individuals with Autism Develop Hyperactive Neuronal Networks

2018 ◽  
Author(s):  
Eric Deneault ◽  
Muhammad Faheem ◽  
Sean H. White ◽  
Deivid C. Rodrigues ◽  
Song Sun ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Large Scale ◽  
De Novo ◽  
Electrode Array ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
High Throughput Phenotyping ◽  
Family Based ◽  
Induced Pluripotent ◽  
Relationship Of

AbstractInduced pluripotent stem cell (iPSC)-derived cortical neurons are increasingly used as a model to study developmental aspects of Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of rare (penetrant) variant(s) and common (weaker) polygenic risk variant(s) to ASD, “isogenic” iPSC-derived neurons from probands and family-based controls, for modeling, is critical. We developed a standardized set of procedures, designed to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD (14 ASD-affected individuals, 3 unaffected siblings, 8 unaffected parents). Heterozygousde novo(7 families; 16p11.2,NRXN1,DLGAP2,CAPRIN1,VIP,ANOS1,THRA) and rare-inherited (2 families;CNTN5,AGBL4) presumed-damaging variants were characterized in ASD risk genes/loci. In three additional families, functional candidates for ASD (SET), and combinations of putative etiologic variants (GLI3/KIF21AandEHMT2/UBE2Icombinations in separate families), were modeled. We used a large-scale multi-electrode array (MEA) as our primary high-throughput phenotyping assay, followed by patch clamp recordings. Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient forCNTN5orEHMT2.Our biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.

scholarly journals CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eric Deneault ◽  
Muhammad Faheem ◽  
Sean H White ◽  
Deivid C Rodrigues ◽  
Song Sun ◽  
...  
Keyword(s):  
De Novo ◽  
Electrode Array ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Editorial Note ◽  
Risk Genes ◽  
Risk Variants ◽  
Induced Pluripotent ◽  
Relationship Of ◽  
Human Ipsc

Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, ‘isogenic’ iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals Leveraging large genomic datasets to illuminate the pathobiology of autism spectrum disorders

2020 ◽  
Vol 46 (1) ◽  
pp. 55-69 ◽  
Author(s):  
Veronica B. Searles Quick ◽  
Belinda Wang ◽  
Matthew W. State
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Developmental Trajectories ◽  
Large Family ◽  
Autism Spectrum ◽  
Chromosomal Structure ◽  
Polygenic Inheritance ◽  
Genomic Studies ◽  
Family Based ◽  
Microarray Studies

Abstract“Big data” approaches in the form of large-scale human genomic studies have led to striking advances in autism spectrum disorder (ASD) genetics. Similar to many other psychiatric syndromes, advances in genotyping technology, allowing for inexpensive genome-wide assays, has confirmed the contribution of polygenic inheritance involving common alleles of small effect, a handful of which have now been definitively identified. However, the past decade of gene discovery in ASD has been most notable for the application, in large family-based cohorts, of high-density microarray studies of submicroscopic chromosomal structure as well as high-throughput DNA sequencing—leading to the identification of an increasingly long list of risk regions and genes disrupted by rare, de novo germline mutations of large effect. This genomic architecture offers particular advantages for the illumination of biological mechanisms but also presents distinctive challenges. While the tremendous locus heterogeneity and functional pleiotropy associated with the more than 100 identified ASD-risk genes and regions is daunting, a growing armamentarium of comprehensive, large, foundational -omics databases, across species and capturing developmental trajectories, are increasingly contributing to a deeper understanding of ASD pathology.

scholarly journals hiPSC-derived 3D Bioprinted Skeletal Muscle Tissue Implants Regenerate Skeletal Muscle Following Volumetric Muscle Loss

2021 ◽  
Author(s):  
Yasamin A. Jodat ◽  
Ting Zhang ◽  
Ziad Al Tanoury ◽  
Tom Kamperman ◽  
Kun Shi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
De Novo ◽  
Induced Pluripotent Stem Cell ◽  
Muscle Loss ◽  
Repair Capacity ◽  
Volumetric Muscle Loss ◽  
Induced Pluripotent ◽  
Long Fibers ◽  
Regenerative Therapies

Abstract Engineering of biomimetic tissue implants provides an opportunity for repairing volumetric muscle loss (VML), beyond a tissue’s innate repair capacity. Here, we present thick, suturable, and pre-vascularized 3D muscle implants containing human induced pluripotent stem cell-derived myogenic precursor cells (hiPSC-MPCs), which can differentiate into skeletal muscle cells while maintaining a self-renewing pool. The formation of contractile myotubes and millimeter-long fibers from hiPSC-MPCs is achieved in chemically, mechanically, and structurally tailored extracellular matrix-based hydrogels, which can serve as scaffolds to ultimately organize the linear fusion of myoblasts. Embedded multi-material bioprinting is used to deposit complex patterns of perfusable vasculatures and aligned hiPSC-MPC channels within an endomysium-like supporting gel to recapitulate muscle architectural integrity in a facile yet highly rapid manner. Moreover, we demonstrate successful graft-host integration and de novo muscle formation upon in vivo implantation of pre-vascularized constructs within a VML model. This work pioneers the engineering of large pre-vascularized hiPSC-derived muscle tissues toward next generation VML regenerative therapies.

scholarly journals Increased burden of deleterious variants in essential genes in autism spectrum disorder

2016 ◽  
Vol 113 (52) ◽  
pp. 15054-15059 ◽  
Author(s):  
Xiao Ji ◽  
Rachel L. Kember ◽  
Christopher D. Brown ◽  
Maja Bućan
Keyword(s):  
Autism Spectrum Disorder ◽  
Large Scale ◽  
De Novo ◽  
Autism Spectrum ◽  
Essential Genes ◽  
Spectrum Disorder ◽  
Model Organisms ◽  
Disease Genes ◽  
Priority List ◽  
Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

scholarly journals The GluN2B subunit represents a major functional determinant of NMDA receptors in human induced pluripotent stem cell-derived cortical neurons

2018 ◽  
Vol 28 ◽  
pp. 105-114 ◽  
Author(s):  
Ioana Neagoe ◽  
Chang Liu ◽  
Alexander Stumpf ◽  
Yanmei Lu ◽  
Dongping He ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nmda Receptors ◽  
Cortical Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Functional Determinant ◽  
Induced Pluripotent

scholarly journals Generation of an induced pluripotent stem cell line from a patient with autism spectrum disorder and SCN2A haploinsufficiency

2019 ◽  
Vol 39 ◽  
pp. 101488 ◽  
Author(s):  
Gabriela Louise de Almeida Sampaio ◽  
Gabriele Louise Soares Martins ◽  
Bruno Diaz Paredes ◽  
Carolina Kymie Vasques Nonaka ◽  
Katia Nunes da Silva ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Stem Cell ◽  
Cell Line ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Stem Cell Line ◽  
Induced Pluripotent

scholarly journals Investigation of de novo mutations in a schizophrenia case-parent trio by induced pluripotent stem cell-based in vitro disease modeling: convergence of schizophrenia- and autism-related cellular phenotypes

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Edit Hathy ◽  
Eszter Szabó ◽  
Nóra Varga ◽  
Zsuzsa Erdei ◽  
Csongor Tordai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dentate Gyrus ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
De Novo ◽  
Disease Onset ◽  
Induced Pluripotent Stem Cell ◽  
Synaptic Function ◽  
De Novo Mutations ◽  
Induced Pluripotent

Abstract Background De novo mutations (DNMs) have been implicated in the etiology of schizophrenia (SZ), a chronic debilitating psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction, and decreased community functioning. Several DNMs have been identified by examining SZ cases and their unaffected parents; however, in most cases, the biological significance of these mutations remains elusive. To overcome this limitation, we have developed an approach of using induced pluripotent stem cell (iPSC) lines from each member of a SZ case-parent trio, in order to investigate the effects of DNMs in cellular progenies of interest, particularly in dentate gyrus neuronal progenitors. Methods We identified a male SZ patient characterized by early disease onset and negative symptoms, who is a carrier of 3 non-synonymous DNMs in genes LRRC7, KHSRP, and KIR2DL1. iPSC lines were generated from his and his parents’ peripheral blood mononuclear cells using Sendai virus-based reprogramming and differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells. We used RNASeq to explore transcriptomic differences and calcium (Ca2+) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines. Results NPCs derived from the SZ patient exhibited transcriptomic differences related to Wnt signaling, neuronal differentiation, axonal guidance and synaptic function, and decreased Ca2+ reactivity to glutamate. Moreover, we could observe increased cellular proliferation and alterations in mitochondrial quantity and morphology. Conclusions The approach of reprograming case-parent trios represents an opportunity for investigating the molecular effects of disease-causing mutations and comparing these in cell lines with reduced variation in genetic background. Our results are indicative of a partial overlap between schizophrenia and autism-related phenotypes in the investigated family. Limitations Our study investigated only one family; therefore, the generalizability of findings is limited. We could not derive iPSCs from two other siblings to test for possible genetic effects in the family that are not driven by DNMs. The transcriptomic and functional assays were limited to the NPC stage, although these variables should also be investigated at the mature neuronal stage.

A MEMS-based measurement system for evaluating the force-length relationship of human induced pluripotent stem cell-derived cardiomyocytes adhered on a substrate

2019 ◽  
Vol 29 (5) ◽  
pp. 055003 ◽  
Author(s):  
Kenei Matsudaira ◽  
Hidetoshi Takahashi ◽  
Kayoko Hirayama-Shoji ◽  
Thanh-Vinh Nguyen ◽  
Takuya Tsukagoshi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Measurement System ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Length Relationship ◽  
Induced Pluripotent ◽  
Relationship Of
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