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Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders

Autism spectrum disorders (ASDs) have been linked to genes with enriched expression in the brain, but it is unclear how these genes converge into cell-type-specific networks. We built a protein-protein interaction network for 13 ASD-associated genes in human excitatory neurons derived from induced pluripotent stem cells (iPSCs). The network contains newly reported interactions and is enriched for genetic and transcriptional perturbations observed in individuals with ASDs. We leveraged the...

Posted by on 2023-03-23

Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism

CONCLUSIONS: We here present an integrated evaluation of all current aspects of gene function and evaluate how abnormalities in chromatin remodeling might relate to the pleiotropic clinical presentation in individual"s" with Helsmoortel-Van der Aa syndrome.

Posted by on 2023-03-22

Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia

The human brain is the most complex structure generated during development. Unveiling the ontogenesis and the intrinsic organization of specific neural networks may represent a key to understanding the physio-pathological aspects of different brain areas. The cortico-thalamic and thalamo-cortical (CT-TC) circuits process and modulate essential tasks such as wakefulness, sleep and memory, and their alterations may result in neurodevelopmental and psychiatric disorders. These pathologies are...

Posted by on 2023-03-20

The promise of autologous and allogeneic cellular therapies in the clinical trials of autism spectrum disorder

Autism spectrum disorder (ASD) is a consortium of developmental conditions. As scientists have not yet identified the exact underlying cause for these disorders, it is not easy to narrow down a singular therapy to propose a reliable cure. The preponderance of research suggests that stem-cell therapy improves aspects of outcome measure scales in patients with ASD; therefore, future studies should give us more confidence in the results. This overview considers the data that have emerged from the...

Posted by on 2023-03-20

Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals

Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an...

Posted by on 2023-03-11

NRXN3 mutations cause developmental delay, movement disorder, and behavioral problems: CRISPR edited cells based WES results

NRXN3geneencodesneurexin-III which is a Neural Cell Adhesion Molecule (NCAM) with important synaptic functions in the brain. Neurexin-III deficiency could affect synapse development, synaptic signaling and neurotransmitter release. Hitherto, there is no related disorder in the OMIM due to NRXN3 mutation. In this study, two unrelated Iranian families with homozygous (NM_001330195.2:c.3995G>A, p.Arg1332His) and compound heterozygous (NM_001330195.2:c.4442G>A, p.Arg1481Gln; c.3142+3A>G) variants in...

Posted by on 2023-03-10

Umbilical cord-derived mesenchymal stromal cell therapy to prevent the development of neurodevelopmental disorders related to low birth weight

Low birth weight (LBW) increases the risk of neurodevelopmental disorders (NDDs) such as attention-deficit/hyperactive disorder and autism spectrum disorder, as well as cerebral palsy, for which no prophylactic measure exists. Neuroinflammation in fetuses and neonates plays a major pathogenic role in NDDs. Meanwhile, umbilical cord-derived mesenchymal stromal cells (UC-MSCs) exhibit immunomodulatory properties. Therefore, we hypothesized that systemic administration of UC-MSCs in the early...

Posted by on 2023-03-07

Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable

Maternal immune activation (MIA) during critical windows of gestation is correlated with long-term neurodevelopmental deficits in the offspring, including increased risk for autism spectrum disorder (ASD) in humans. Interleukin 6 (IL-6) derived from the gestational parent is one of the major molecular mediators by which MIA alters the developing brain. In this study, we establish a human three-dimensional (3D) in vitro model of MIA by treating induced pluripotent stem cell-derived dorsal...

Posted by on 2023-03-06

Autism-like behavior of murine offspring induced by prenatal exposure to progestin is associated with gastrointestinal dysfunction due to claudin-1 suppression

Autism spectrum disorders (ASD) are associated with the contribution of many prenatal risk factors; in particular, the sex hormone progestin and vitamin D receptor (VDR) are associated with gastrointestinal (GI) symptoms in ASD development, although the related mechanism remains unclear. We investigated the possible role and mechanism of progestin 17-hydroxyprogesterone caproate (17-OHPC) exposure-induced GI dysfunction and autism-like behaviours (ALB) in mouse offspring. An intestine-specific...

Posted by on 2023-03-01

Modeling Autism Spectrum Disorders with Induced Pluripotent Stem Cell-Derived Brain Organoids

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders that affect communication and social interactions and present with restricted interests and repetitive behavior patterns. The susceptibility to ASD is strongly influenced by genetic/heritable factors; however, there is still a large gap in understanding the cellular and molecular mechanisms underlying the neurobiology of ASD. Significant progress has been made in identifying ASD risk genes and the possible...

Posted by on 2023-02-25

The people behind the papers - Rana Fetit and David Price

16p11.2 microdeletions are genetically associated with autism spectrum disorder (ASD), but the links to the various patient phenotypes are not well understood. In a new paper in Development, Rana Fetit and colleagues use ventral organoids derived from induced pluripotent stem cells to dissect the effect of 16p11.2 microdeletions on interneuron development. We caught up with corresponding author Rana Fetit and group leader David Price to find out more about their research.

Posted by on 2023-02-24

16p11.2 deletion accelerates subpallial maturation and increases variability in human iPSC-derived ventral telencephalic organoids

Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases. However, few studies investigate the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we have investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation...

Posted by on 2023-02-24

Combined omic analyses reveal autism-linked NLGN3 gene as a key developmental regulator of GnRH neuron biology and disease

Gonadotropin releasing hormone (GnRH) deficiency is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GnRH deficiency (GD). Here, we combined bioinformatic analyses of immortalized and primary embryonic GnRH neuron transcriptomes with exome sequencing from GD patients to...

Posted by on 2023-02-22

Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder

CONCLUSIONS: We identified an important role for SETBP1 in controlling forebrain progenitor expansion and neurogenic differentiation. Our study establishes a novel regulatory link between SETBP1 and Wnt/β-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder.

Posted by on 2023-02-22

Structure-based developmental toxicity and ASD-phenotypes of bisphenol A analogues in embryonic zebrafish

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has become more prevalent in recent years. Environmental endocrine disruptor bisphenol A (BPA) has been linked to ASD. BPA analogues (BPs) are structure-modified substitutes widely used as safer alternatives in consumer products, yet few studies have explored the developmental neurotoxicity (DNT) of BPA analogues. In the present study, we used the larval zebrafish model to assess the DNT effects of BPA and its analogues. Our...

Posted by on 2023-02-22

Prenatal exposure of diabetes and progestin-mediated autistic biomarker in peripheral blood mononuclear cells

Despite the importance of early diagnosis and intervention, the diagnosis of autism spectrum disorders (ASDs) remains delayed as it is mostly based on clinical symptoms and abnormal behaviours appearing after 2 years of age. Identification of autistic markers remains a top priority in achieving an early and effective ASD diagnosis. We have previously reported that prenatal exposure of hormones or diabetes triggers epigenetic changes and oxidative stress, resulting in gene suppression with...

Posted by on 2023-02-14

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including...

Posted by on 2023-02-14

Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells

CONCLUSION: Our data provide evidence for cell specific effects of acute IL-6 exposure in a human model system, ultimately suggesting that microglia-NPC co-culture models are required to study how IL-6 influences human cortical neural progenitor cell development in vitro.

Posted by on 2023-02-13

Stem Cell-Based Organoid Models of Neurodevelopmental Disorders

The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror...

Posted by on 2023-02-09

In vivo models to study neurogenesis and associated neurodevelopmental disorders-Microcephaly and autism spectrum disorder

The genesis and functioning of the central nervous system are one of the most intricate and intriguing aspects of embryogenesis. The big lacuna in the field of human CNS development is the lack of accessibility of the human brain for direct observation during embryonic and fetal development. Thus, it is imperative to establish alternative animal models to gain deep mechanistic insights into neurodevelopment, establishment of neural circuitry, and its function. Neurodevelopmental events such as...

Posted by on 2023-02-08

Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice

Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice...

Posted by on 2023-02-08

Safety and Efficacy of Allogeneic Umbilical Cord Blood Therapy for Global Development Delay and Intellectual Disability

Most pediatric patients with global developmental delay (GDD) or intellectual disability (ID) have disrupted development. Since allogeneic umbilical cord blood (UCB) may exert neurotrophic effects, a prospective clinical trial was conducted to assess the efficacy and safety of UCB therapy for GDD and ID. A total of 13 children (ages 23-149 months) with GDD and ID were enrolled and followed up for 12 months. Under criteria of histocompatibility and cell number, allogeneic UCB units were selected...

Posted by on 2023-02-03

Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders

Genome-wide association studies reveal the complex polygenic architecture underlying psychiatric disorder risk, but there is an unmet need to validate causal variants, resolve their target genes(s), and explore their functional impacts on disorder-related mechanisms. Disorder-associated loci regulate transcription of target genes in a cell type- and context-specific manner, which can be measured through expression quantitative trait loci. In this review, we discuss methods and insights from...

Posted by on 2023-01-19

Disruption of DDX53 coding sequence has limited impact on iPSC-derived human NGN2 neurons

CONCLUSION: DDX53-3TC mutation does not alter NGN2 neuronal function in these experiments, suggesting that synaptic deficits causing ASD are unlikely in this cell type.

Posted by on 2023-01-12

ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers

ZNF462 haploinsufficiency is linked to Weiss-Kruszka syndrome, a genetic disorder characterized by neurodevelopmental defects, including autism. Though conserved in vertebrates and essential for embryonic development, the molecular functions of ZNF462 remain unclear. We identified its murine homologue ZFP462 in a screen for mediators of epigenetic gene silencing. Here we show that ZFP462 safeguards neural lineage specification of mouse embryonic stem cells (ESCs) by targeting the H3K9-specific...

Posted by on 2023-01-05

Adult hippocampal neurogenesis and social behavioural deficits in the R451C Neuroligin3 mouse model of autism are reverted by the antidepressant fluoxetine

Neuron generation persists throughout life in the hippocampus but is altered in animal models of neurological and neuropsychiatric diseases, suggesting that disease-associated decline in cognitive and emotional hippocampal-dependent behaviours might be functionally linked with dysregulation of postnatal neurogenesis. Depletion of the adult neural stem/progenitor cell (NSPCs) pool and neurogenic decline have been recently described in mice expressing synaptic susceptibility genes associated with...

Posted by on 2022-12-30

Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons

CONCLUSIONS: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our...

Posted by on 2022-12-29

The autism risk factor CHD8 is a chromatin activator in human neurons and functionally dependent on the ERK-MAPK pathway effector ELK1

The chromodomain helicase DNA-binding protein CHD8 is the most frequently mutated gene in autism spectrum disorder. Despite its prominent disease involvement, little is known about its molecular function in the human brain. CHD8 is a chromatin regulator which binds to the promoters of actively transcribed genes through genomic targeting mechanisms which have yet to be fully defined. By generating a conditional loss-of-function and an endogenously tagged allele in human pluripotent stem cells, we...

Posted by on 2022-12-27

Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN- response pathway activation and senescence in differentiated microglia; an early life stress model

One form of early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in later life. Increasingly, the importance of microglia in these disorders is recognized. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-exposure of human iPS-microglia to GCs during primitive hematopoiesis (the critical stage...

Posted by on 2022-12-26

CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states....

Posted by on 2022-12-20

Generation of an induced pluripotent stem cell line (IPCASi001-A) from an autism spectrum disorder individual without intellectual disability

Autism spectrum disorder (ASD) is a highly inheritable neurodevelopmental disorder that causes diverse deficits in social communication and restricted repetitive sensorimotor behaviors. Here, we studied a human-induced pluripotent cell line from an autistic patient with impaired social function and a normal intelligence quotient (IQ > 70). The cell line was validated by its morphology, gene expression, and potential to differentiate into three germ layers. This model can be used to explore the...

Posted by on 2022-12-11

Spatiotemporal dynamics of 5-HT6 receptor ciliary localization during mouse brain development

The serotonin 5-HT(6) receptor (5-HT(6)R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT(6)R. Here, we used transgenic mice expressing a GFP-tagged 5-HT(6)R under the control of its endogenous promoter (Knock-in) as...

Posted by on 2022-12-10

Decoding microRNAs in autism spectrum disorder

Autism spectrum disorder (ASD)-a congenital mental disorder accompanied by social dysfunction and stereotyped behaviors-has attracted a great deal of attention worldwide. A combination of genetic and environmental factors may determine the pathogenesis of ASD. Recent research of multiple ASD models indicates that microRNAs (miRNAs) play a central role at the onset and progression of ASD by repressing the translation of key mRNAs in neural development and functions. As such, miRNAs show great...

Posted by on 2022-12-02

Partial changes in apoptotic pathways in hippocampus and hypothalamus of Cc2d1a heterozygous

Alterations in the apoptosis pathway have been linked to changes in serotonin levels seen in autistic patients. Cc2d1a is a repressor of the HTR1A gene involved in the serotonin pathway. The hippocampus and hypothalamus of Cc2d1a ± mice were analyzed for the expression of apoptosis markers (caspase 3, 8 and 9). Gender differences were observed in the expression levels of the three caspases consistent with some altered activity in the open-field assay. The number of apoptotic cells was...

Posted by on 2022-12-01

16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons

16p13.11 copy number variants (CNVs) have been associated with autism, schizophrenia, psychosis, intellectual disability, and epilepsy. The majority of 16p13.11 deletions or duplications occur within three well-defined intervals, and despite growing knowledge of the functions of individual genes within these intervals, the molecular mechanisms that underlie commonly observed clinical phenotypes remain largely unknown. Patient-derived, induced pluripotent stem cells (iPSCs) provide a platform for...

Posted by on 2022-11-21

Abnormal Chromatin Folding in the Molecular Pathogenesis of Epilepsy and Autism Spectrum Disorder: a Meta-synthesis with Systematic Searching

How DNA is folded and packaged in nucleosomes is an essential regulator of gene expression. Abnormal patterns of chromatin folding are implicated in a wide range of diseases and disorders, including epilepsy and autism spectrum disorder (ASD). These disorders are thought to have a shared pathogenesis involving an imbalance in the number of excitatory-inhibitory neurons formed during neurodevelopment; however, the underlying pathological mechanism behind this imbalance is poorly understood....

Posted by on 2022-11-11

The DNA Methylation in Neurological Diseases

DNA methylation is critical for the normal development and functioning of the human brain, such as the proliferation and differentiation of neural stem cells, synaptic plasticity, neuronal reparation, learning, and memory. Despite the physical stability of DNA and methylated DNA compared to other epigenetic modifications, some DNA methylation-based biomarkers have translated into clinical practice. Increasing reports indicate a strong association between DNA methylation profiles and various...

Posted by on 2022-11-11

Elevation of SHANK3 Levels by Antisense Oligonucleotides Directed Against the 3'-UTR of the Human SHANK3 mRNA

SHANK3 is a member of the SHANK family of scaffolding proteins that localize to the postsynaptic density of excitatory synapses. Mutations within the SHANK3 gene or SHANK3 haploinsufficiency is thought to be one of the major causes for Phelan-McDermid Syndrome (PMDS) that is characterized by a broad spectrum of autism-related behavioral alterations. Several approaches have already been proposed to elevate SHANK3 protein levels in PMDS patients like transcriptional activation or inhibition of...

Posted by on 2022-11-10

Changes in the geometry and robustness of diffusion tensor imaging networks: Secondary analysis from a randomized controlled trial of young autistic children receiving an umbilical cord blood infusion

Diffusion tensor imaging (DTI) has been used as an outcome measure in clinical trials for several psychiatric disorders but has rarely been explored in autism clinical trials. This is despite a large body of research suggesting altered white matter structure in autistic individuals. The current study is a secondary analysis of changes in white matter connectivity from a double-blind placebo-control trial of a single intravenous cord blood infusion in 2-7-year-old autistic children (1). Both...

Posted by on 2022-11-10

Ex vivo expansion of natural killer cells for hematological cancer immunotherapy: a systematic review and meta-analysis

The present systematic review aimed to investigate natural killer (NK) cell ex vivo expansion protocols within the scope of clinical trials targeting hematological cancer and to conduct a meta-analysis to assess the effect of NK cell infusion on survival. Research articles of clinical studies in which cell products produced by ex vivo expansion, consisting of a certain amount of NK cells and infused to patients with hematological cancer, were included in the systematic review. We conducted a...

Posted by on 2022-11-05

Issues for patchy tissues: defining roles for gut-associated lymphoid tissue in neurodevelopment and disease

Individuals diagnosed with neurodevelopmental conditions such as autism spectrum disorder (ASD; autism) often experience tissue inflammation as well as gastrointestinal dysfunction, yet their underlying causes remain poorly characterised. Notably, the largest components of the body's immune system, including gut-associated lymphoid tissue (GALT), lie within the gastrointestinal tract. A major constituent of GALT in humans comprises secretory lymphoid aggregates known as Peyer's patches that...

Posted by on 2022-10-30

Postnatal Conditional Deletion of Bcl11b in Striatal Projection Neurons Mimics the Transcriptional Signature of Huntington's Disease

The dysregulation of striatal gene expression and function is linked to multiple diseases, including Huntington's disease (HD), Parkinson's disease, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neurons in the striatum and are critical to motor control. The transcription factor, Bcl11b (also known as Ctip2), is required for striatal development, but the function of Bcl11b in adult MSNs in vivo has not been...

Posted by on 2022-10-27

Generation of induced pluripotent stem cell lines from nonaffected parents and monozygotic triplets affected with autism spectrum disorder and epilepsy

We have generated induced pluripotent stem cell (iPSC) lines from monozygotic triplets with a rare homozygous mutation in NAPB gene (c.354+2T>G). iPSC lines were also generated from their consanguineous parents who were both heterozygous for the inherited NAPB mutation. The iPSC lines were generated using non-integrating Sendai viral vectors. All iPSC lines showed prototypical stem cell morphology, expressed pluripotency markers and were able to differentiate to all three germ lineages. These...

Posted by on 2022-10-22

Oxytocin accelerates tight junction formation and impairs cellular migration in 3D spheroids: evidence from Gapmer-induced exon skipping

Oxytocin (OXT) is a neuropeptide that has been associated with neurological diseases like autism, a strong regulating activity on anxiety and stress-related behavior, physiological effects during pregnancy and parenting, and various cellular effects in neoplastic tissue. In this study, we aimed to unravel the underlying mechanism that OXT employs to regulate cell-cell contacts, spheroid formation, and cellular migration in a 3D culture model of human MLS-402 cells. We have generated a labeled...

Posted by on 2022-10-20

CASK loss of function differentially regulates neuronal maturation and synaptic function in human induced cortical excitatory neurons

Loss-of-function (LOF) mutations in CASK cause severe developmental phenotypes, including microcephaly with pontine and cerebellar hypoplasia, X-linked intellectual disability, and autism. Unraveling the pathological mechanisms of CASK-related disorders has been challenging owing to limited human cellular models to study the dynamic roles of this molecule during neuronal maturation and synapse development. Here, we investigate cell-autonomous functions of CASK in cortical excitatory induced...

Posted by on 2022-10-20

Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene MECP2 that is a global transcriptional regulator. Mutations in the methyl-CpG binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA. Here, we investigate the effect of a novel MECP2 L124W missense mutation in the MBD of an atypical RTT patient with preserved speech in comparison to severe MECP2 null mutations. L124W protein had a limited...

Posted by on 2022-10-17

Maturation and circuit integration of transplanted human cortical organoids

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease^(1-5). However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related...

Posted by on 2022-10-12

Autism-associated CHD8 keeps proliferation of human neural progenitors in check by lengthening the G1 phase of the cell cycle

De novo mutations (DNMs) in chromodomain helicase DNA binding protein 8 (CHD8) are associated with a specific subtype of autism characterized by enlarged heads and distinct cranial features. The vast majority of these DNMs are heterozygous loss-of-function mutations with high penetrance for autism. CHD8 is a chromatin remodeler that preferentially regulates expression of genes implicated in early development of the cerebral cortex. How CHD8 haploinsufficiency alters the normal developmental...

Posted by on 2022-10-12

Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial...

Posted by on 2022-10-06

Neuronal hyperexcitability and ion channel dysfunction in CDKL5-deficiency patient iPSC-derived cortical organoids

Early epilepsy is a prominent feature in patients with CDKL5-deficiency disorder (CDD). The underlying mechanism for excessive excitability in CDD is largely unknown. The brain organoid model has been recently developed to resemble many critical features of early human brain development. Here, we used a brain organoid model to investigate the cellular electrophysiological basis for hyper-excitability in CDD patients. Our study employed cortical organoids derived from two CDD patients harboring...

Posted by on 2022-10-06

Modeling Human Cerebellar Development In Vitro in 2D Structure

The precise and timely development of the cerebellum is crucial not only for accurate motor coordination and balance but also for cognition. In addition, disruption in cerebellar development has been implicated in many neurodevelopmental disorders, including autism, attention deficit-hyperactivity disorder (ADHD), and schizophrenia. Investigations of cerebellar development in humans have previously only been possible through post-mortem studies or neuroimaging, yet these methods are not...

Posted by on 2022-10-03

Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring

The prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with...

Posted by on 2022-10-03

Publisher Correction: Brain charts for the human lifespan

No abstract

Posted by on 2022-09-23

p27kip1 Modulates the Morphology and Phagocytic Activity of Microglia

p27^(kip1) is a multifunctional protein that promotes cell cycle exit by blocking the activity of cyclin/cyclin-dependent kinase complexes as well as migration and motility via signaling pathways that converge on the actin and microtubule cytoskeleton. Despite the broad characterization of p27^(kip1) function in neural cells, little is known about its relevance in microglia. Here, we studied the role of p27^(kip1) in microglia using a combination of in vitro and in situ approaches. While the...

Posted by on 2022-09-23

Molecular diversity and phenotypic pleiotropy of ancient genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their contemporary impacts on pathophysiology of Modern Humans

Timelines of population-level effects of viruses on humans varied from the evolutionary scale of million years to contemporary spread of viral infections. Correspondingly, these events are exemplified by: (i) emergence of human endogenous retroviruses (HERVs) from ancient germline infections leading to stable integration of viral genomes into human chromosomes; and (ii) wide-spread viral infections reaching a global pandemic state such as the COVID-19 pandemic. Despite significant efforts,...

Posted by on 2022-09-19

Endothelial cells regulated by RNF20 orchestrate the proliferation and differentiation of neural precursor cells during embryonic development

The intimate communication between the vascular and nervous systems is critical for maintaining central nervous system (CNS) development. However, whether cerebrovascular endothelial cells (ECs) can orchestrate neural precursor cell (NPC) proliferation and differentiation, and the identity of the signals involved therein, is unclear. Here, we find that the development of ECs is often accompanied by DNA damage. RNF20, an E3 ubiquitin ligase, is required for the DNA damage response (DDR). The...

Posted by on 2022-09-14

miR-124- and let-7-Mediated Reprogram of Human Fibroblasts into SST Interneurons

Many neurological disorders stem from defects in or the loss of specific neurons. Dysfunction of γ-aminobutyric acid (GABA)ergic interneurons may cause a variety of neurological and psychiatric disorders such as epilepsy, autism, Alzheimer's disease, and depression. Unlike other types of neurons, which can be generated relatively easily by direct reprogramming, it is difficult to generate GABAergic neurons by traditional methods. Neuronal transdifferentiation of fibroblasts mediated by...

Posted by on 2022-09-08

Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models

Down syndrome (DS), driven by an extra copy of chromosome 21 (HSA21), and fragile X syndrome (FXS), driven by loss of the RNA-binding protein FMRP, are two common genetic causes of intellectual disability and autism. Based upon the number of DS-implicated transcripts bound by FMRP, we hypothesize that DS and FXS may share underlying mechanisms. Comparing DS and FXS human pluripotent stem cell (hPSC) and glutamatergic neuron models, we identify increased protein expression of select targets and...

Posted by on 2022-09-07

A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism

CONCLUSIONS: By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial. The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases.

Posted by on 2022-09-06

Generation and characterization of iPSC lines (UOHi003-A, UOHi002-A) from a patient with SHANK3 mutation and her healthy mother

Phelan-McDermid syndrome (PMS) is a rare genetic condition that causes global developmental disability, delayed or absent speech, and an autism spectrum disorder. The loss of function of one copy of SHANK3, which codes for a scaffolding protein found in the postsynaptic density of synapses, has been identified as the main cause of PMS. We report the generation and characterization of two induced pluripotent stem cell (iPSC) lines derived from one patient with a SHANK3 mutation and the patient's...

Posted by on 2022-08-31

Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation

CONCLUSION: Our findings demonstrate that the clinical phenotype of STAMBP mutations is highly variable, and patients with different STAMBP mutations show differences in the severity of symptoms. The STAMBP missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.

Posted by on 2022-08-29

Human-Induced Pluripotent Stem Cell Technology: Toward the Future of Personalized Psychiatry

The polygenic and multifactorial nature of many psychiatric disorders has hampered implementation of the personalized medicine approach in clinical practice. However, induced pluripotent stem cell (iPSC) technology has emerged as an innovative tool for patient-specific disease modeling to expand the pathophysiology knowledge and treatment perspectives in the last decade. Current technologies enable adult human somatic cell reprogramming into iPSCs to generate neural cells and direct neural cell...

Posted by on 2022-08-26

Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal...

Posted by on 2022-08-26

DNA Methylation Profiles of GAD1 in Human Cerebral Organoids of Autism Indicate Disrupted Epigenetic Regulation during Early Development

DNA methylation profiling has become a promising approach towards identifying biomarkers of neuropsychiatric disorders including autism spectrum disorder (ASD). Epigenetic markers capture genetic risk factors and diverse exogenous and endogenous factors, including environmental risk factors and complex disease pathologies. We analysed the differential methylation profile of a regulatory region of the GAD1 gene using cerebral organoids generated from induced pluripotent stem cells (iPSCs) from...

Posted by on 2022-08-26

Abnormal vestibular brainstem structure and function in an animal model of autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to...

Posted by on 2022-08-19

Serious Adverse Events Have Not Been Reported with Spinal Intrathecal Injection of Mesenchymal Stem Cells: A Systematic Review

CONCLUSION: Properly performed spinal intrathecal injection of MSCs is exceedingly safe, with no serious adverse events reported based on our exhaustive literature search.

Posted by on 2022-08-18

CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD

We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized...

Posted by on 2022-08-18

Correlation Between CD133+ Stem Cells and Clinical Improvement in Patients with Autism Spectrum Disorders Treated with Intrathecal Bone Marrow-derived Mononuclear Cells

Autism spectrum disorders (ASDs) are a group of neurodevelopmental pathologies characterized by social and communication deficits, for which treatments are limited. Cell therapies, including intrathecal (IT) administration of bone marrow (BM) mononuclear cells (BM-MNC), improves symptoms in patients with ASD. Twenty-four patients diagnosed with ASD, according to the Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition (DSM-IV-TR) criteria, were autologously treated...

Posted by on 2022-08-12

Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Identifying causative gene(s) within disease-associated large genomic regions of copy-number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation,...

Posted by on 2022-08-05

Haste Makes Waste: There Is No Solid Evidence to Translate the Use of Stem Cells into Clinical Practice for Children with Autism Spectrum Disorder

Increasingly, private clinics around the world offer stem cell therapy as a therapeutic approach for autism spectrum disorder (ASD) [...].

Posted by on 2022-07-27

Bridging between Mouse and Human Enhancer-Promoter Long-Range Interactions in Neural Stem Cells, to Understand Enhancer Function in Neurodevelopmental Disease

Non-coding variation in complex human disease has been well established by genome-wide association studies, and is thought to involve regulatory elements, such as enhancers, whose variation affects the expression of the gene responsible for the disease. The regulatory elements often lie far from the gene they regulate, or within introns of genes differing from the regulated gene, making it difficult to identify the gene whose function is affected by a given enhancer variation. Enhancers are...

Posted by on 2022-07-27

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Drosophila models of neurological disease contribute tremendously to research progress due to the high conservation of human disease genes, the powerful and sophisticated genetic toolkit, and the rapid generation time. Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability and autism spectrum disorders, and the Drosophila FXS disease model has been critical for the genetic screening discovery of new intercellular secretion mechanisms. Here, we focus on the...

Posted by on 2022-07-26

Microglia homeostasis mediated by epigenetic ARID1A regulates neural progenitor cells response and leads to autism-like behaviors

Microglia are resident macrophages of the central nervous system that selectively emerge in embryonic cortical proliferative zones and regulate neurogenesis by altering molecular and phenotypic states. Despite their important roles in inflammatory phagocytosis and neurodegenerative diseases, microglial homeostasis during early brain development has not been fully elucidated. Here, we demonstrate a notable interplay between microglial homeostasis and neural progenitor cell signal transduction...

Posted by on 2022-07-20

Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD). We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions. Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations...

Posted by on 2022-07-15

Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling

CHD8 is an ATP-dependent chromatin-remodeling factor whose monoallelic mutation defines a subtype of autism spectrum disorders (ASDs). Previous work found that CHD8 is required for the maintenance of hematopoiesis by integrating ATM-P53-mediated survival of hematopoietic stem/progenitor cells (HSPCs). Here, by using Chd8^(F/F)Mx1-Cre combined with a Trp53^(F/F) mouse model that suppresses apoptosis of Chd8^(-/-) HSPCs, we identify CHD8 as an essential regulator of erythroid differentiation....

Posted by on 2022-07-13

Cerebral organoids containing an AUTS2 missense variant model microcephaly

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth,...

Posted by on 2022-07-08

Tbr1 Misexpression Alters Neuronal Development in the Cerebral Cortex

Changes in the transcription factor (TF) expression are critical for brain development, and they may also underlie neurodevelopmental disorders. Indeed, T-box brain1 (Tbr1) is a TF crucial for the formation of neocortical layer VI, and mutations and microdeletions in that gene are associated with malformations in the human cerebral cortex, alterations that accompany autism spectrum disorder (ASD). Interestingly, Tbr1 upregulation has also been related to the occurrence of ASD-like symptoms,...

Posted by on 2022-07-05

Isolation of Mouse Embryonic Neural Stem Cells and Characterization of Neural Stem Markers by Flow Cytometry

Neurogenesis is outlined as a process in which new neurons are generated from neural stem cells (NSCs). This process comprises proliferation and fate specification of NSCs, migration of newborn neurons, and their maturation. Defects in embryonic neurogenesis have emerged as a key mechanism underlying neurodevelopmental disorders such as autism spectrum disorders and intellectual disability. An impairment in neurogenesis has also been observed in neurodegenerative disorders such as Huntington's...

Posted by on 2022-07-01

MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects....

Posted by on 2022-06-29

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered...

Posted by on 2022-06-27

Modeling tuberous sclerosis complex with human induced pluripotent stem cells

CONCLUSIONS: In this review, we present an overview of the recent progress in modeling TSC with human iPSC models, the existing limitations, and potential directions for future research.

Posted by on 2022-06-27

Dynamic Interrogation of Stochastic Transcriptome Trajectories Using Disease Associated Genes Reveals Distinct Origins of Neurological and Psychiatric Disorders

The advent of open access to genomic data offers new opportunities to revisit old clinical debates while approaching them from a different angle. We examine anew the question of whether psychiatric and neurological disorders are different from each other by assessing the pool of genes associated with disorders that are understood as psychiatric or as neurological. We do so in the context of transcriptome data tracked as human embryonic stem cells differentiate and become neurons. Building upon...

Posted by on 2022-06-20

Zika virus induces FOXG1 nuclear displacement and downregulation in human neural progenitors

Congenital alterations in the levels of the transcription factor Forkhead box g1 (FOXG1) coding gene trigger "FOXG1 syndrome," a spectrum that recapitulates birth defects found in the "congenital Zika syndrome," such as microcephaly and other neurodevelopmental conditions. Here, we report that Zika virus (ZIKV) infection alters FOXG1 nuclear localization and causes its downregulation, thus impairing expression of genes involved in cell replication and apoptosis in several cell models, including...

Posted by on 2022-06-17

Cell line specific alterations in genes associated with dopamine metabolism and signaling in midbrain dopaminergic neurons derived from 22q11.2 deletion carriers with elevated dopamine synthesis capacity

Microdeletions at the 22q11.2 locus are associated with increased risk for schizophrenia. Recent work has demonstrated that antipsychotic naïve 22q11.2 carriers display elevated levels of dopamine synthesis capacity (DSC) as assessed by ^(18)F-DOPA PET imaging. While this is consistent with a role for abnormal dopamine function in schizophrenia, it is unclear what molecular changes may be associated with this neuro-imaging endophenotype, and moreover, if these alterations occur independently of...

Posted by on 2022-06-14

Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder

Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci...

Posted by on 2022-06-10

Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells

Cannabis use in the United States is increasing, with highest consumption among men at their peak reproductive years. We previously demonstrated widespread changes in sperm DNA methylation with cannabis exposure in humans and rats, including genes important in neurodevelopment. Here, we use an in vitro human spermatogenesis model to recapitulate chronic cannabis use and assess DNA methylation at imprinted and autism spectrum disorder (ASD) candidate genes in spermatogonial stem cell (SSC)- and...

Posted by on 2022-06-10

Thirty Years' History since the Discovery of Pax6: From Central Nervous System Development to Neurodevelopmental Disorders

Pax6 is a sequence-specific DNA binding transcription factor that positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system (CNS). As indicated by the morphological and functional abnormalities in spontaneous Pax6 mutant rodents, Pax6 plays pivotal roles in various biological processes in the CNS. At the initial stage of CNS development, Pax6 is responsible for brain patterning along the anteroposterior and...

Posted by on 2022-06-10

Across Dimensions: Developing 2D and 3D Human iPSC-Based Models of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. FXS is caused by a cytosine-guanine-guanine (CGG) trinucleotide repeat expansion in the untranslated region of the FMR1 gene leading to the functional loss of the gene's protein product FMRP. Various animal models of FXS have provided substantial knowledge about the disorder. However, critical limitations exist in replicating the pathophysiological mechanisms. Human induced...

Posted by on 2022-06-10

Targeting NMDA receptors in neuropsychiatric disorders by drug screening on human neurons derived from pluripotent stem cells

NMDA receptors (NMDARs), a prominent subtype of glutamatergic receptors, are implicated in the pathogenesis and development of neuropsychiatric disorders such as epilepsy, intellectual disability, autism spectrum disorder, and schizophrenia, and are therefore a potential therapeutic target in treating these disorders. Neurons derived from induced pluripotent stem cells (iPSCs) have provided the opportunity to investigate human NMDARs in their native environment. In this review, we describe the...

Posted by on 2022-06-10

Autism-associated protein POGZ controls ESCs and ESC neural induction by association with esBAF

CONCLUSIONS: The data suggest that POGZ is both a transcription factor and a genome regulator, and its loss leads to defects in neural induction and neurogenesis.

Posted by on 2022-06-01

Phosphatidylinositol transfer protein/planar cell polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration

The neocortex expands explosively during embryonic development. The earliest populations of neural stem cells (NSCs) form a thin pseudostratified epithelium whose contour determines that of the adult neocortex. Neocortical complexity is accompanied by disproportional expansion of the NSC layer in its tangential dimension to increase tissue surface area. How such disproportional expansion is controlled remains unknown. We demonstrate that a phosphatidylinositol transfer protein...

Posted by on 2022-06-01

Mapping cis-regulatory elements in human neurons links psychiatric disease heritability and activity-regulated transcriptional programs

Genome-wide association studies (GWASs) have identified hundreds of loci associated with psychiatric diseases, yet there is a lack of understanding of disease pathophysiology. Common risk variants can shed light on the underlying molecular mechanisms; however, identifying causal variants remains challenging. We map cis-regulatory elements in human neurons derived from pluripotent stem cells. This system allows us to determine enhancers that activate the transcription of neuronal...

Posted by on 2022-06-01

Role of Brain Modulators in Neurodevelopment: Focus on Autism Spectrum Disorder and Associated Comorbidities

Autism spectrum disorder (ASD) and associated neurodevelopmental disorders share similar pathogenesis and clinical features. Pathophysiological changes in these diseases are rooted in early neuronal stem cells in the uterus. Several genetic and environmental factors potentially perturb neurogenesis and synaptogenesis processes causing incomplete or altered maturation of the brain that precedes the symptomology later in life. In this review, the impact of several endogenous neuromodulators and...

Posted by on 2022-05-28

Autism NPCs from both idiopathic and CNV 16p11.2 deletion patients exhibit dysregulation of proliferation and mitogenic responses

Neural precursor cell (NPC) dysfunction has been consistently implicated in autism. Induced pluripotent stem cell (iPSC)-derived NPCs from two autism groups (three idiopathic [I-ASD] and two 16p11.2 deletion [16pDel]) were used to investigate if proliferation is commonly disrupted. All five individuals display defects, with all three macrocephalic individuals (two 16pDel, one I-ASD) exhibiting hyperproliferation and the other two I-ASD subjects displaying hypoproliferation. NPCs were challenged...

Posted by on 2022-05-27

Stem Cells from Human Exfoliated Deciduous Teeth Ameliorate Autistic-Like Behaviors of SHANK3 Mutant Beagle Dogs

Mesenchymal stem cell-based therapy has emerged as a great potential approach to treat individuals with autism spectrum disorders (ASD), a group of developmental disabilities characterized by impairments in social interaction and communication. Stem cells from human exfoliated deciduous teeth (SHED), holding earlier developing characteristics, have immune-modulatory and anti-inflammatory properties. To investigate whether SHED transplantation can rescue autistic-like symptoms in SHANK3 mutant...

Posted by on 2022-05-24

Efficacy and Safety of Stem Cell Therapy in Children With Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

CONCLUSIONS: The results of this meta-analysis suggested that stem cell therapy for children with autism might be safe and effective. However, the evidence was compromised by the limitations in current study size, lacking standardized injection routes and doses of stem cells, as well as shortages in diagnostic tools and long period follow-up studies. Hence, it calls for more studies to systematically confirm the efficacy and safety of stem cell therapy for children with autism spectrum...

Posted by on 2022-05-23

Safety of Combined Autistic Spectrum Disorders Treatment with Umbilical Cord Mesenchymal Stem Cells Application: Clinical Investigation

No abstract

Posted by on 2022-05-23

Generation of a MIR5004 knockout cell line from human induced pluripotent stem cells by CRISPR/Cas9 gene editing

MIR5004 is located in the intronic region of SYNGAP1, a genetic risk factor for Autism Spectrum Disorders (ASD), and co-expressed with SYNGAP1 in brain tissue, which indicates that MIR5004 may play an important role in ASD pathogenesis through the regulation of SYNGAP1. Here, we generated a MIR5004 knockout human induced pluripotent stem cell (iPSC) line SHCDCLi001-B. SHCDCLi001-B shows expression of pluripotent markers, three lineage differentiation capacity, normal morphology and karyotypes,...

Posted by on 2022-05-16

Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells

Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by expansion of a CGG trinucleotide repeat in the 5'-UTR of the Fragile X Mental Retardation-1 (FMR1) gene. Epigenetic silencing of FMR1 results in loss of the Fragile X Mental Retardation Protein (FMRP). Although most studies to date have focused on excitatory neurons, recent evidence suggests that GABAergic inhibitory networks are also affected. To investigate human...

Posted by on 2022-05-13

Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of fragile X syndrome

CONCLUSIONS: Our data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes likely through modulating adult neurogenic niche that impact adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.

Posted by on 2022-05-13

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