Optimizing neuronal differentiation from induced pluripotent stem cells to model ASD

Kim, Dae Sung; Ross, P. Joel; Zaslavsky, Kirill; Ellis, James

doi:10.3389/fncel.2014.00109

Cited by 52 publications

(47 citation statements)

References 133 publications

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“…Although there are no publications to date describing the CNVs described here, hiPSCs have been used to model NDs that include autistic features: neurons differentiated from hiPSCs of affected individuals or from genetically modified hiPSCs exhibited disease-related phenotypes, such as fewer synapses, smaller soma size, deficits in calcium signalling and in spontaneous excitatory synaptic communication, when compared with unaffected control neurons 148. hiPSC-derived neurons in patients with SZ showed an aberrant migration, increased oxidative stress,149 significantly reduced neuronal connectivity, reduced neurite outgrowth, reduced dendritic levels of PSD95 and altered gene expression profiles; interestingly, key cellular and molecular elements of the SZ phenotype were ameliorated following treatment of SZ hiPSC neurons with the antipsychotic loxapine 150…”

Section: Impact Of Cnvsmentioning

confidence: 99%

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

2015

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Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice.

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Section: Impact Of Cnvsmentioning

confidence: 99%

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

2015

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“…iPSC lines, normally produced from skin fibroblasts, have also been generated from peripheral blood mononuclear cells (PBMCs) isolated from children with autism, to serve as a less invasive source of starting material [85]. This is an emerging field that holds great potential, and the optimization and standardization of differentiation protocols will allow for the rapid, efficient generation of desired cell types used for mechanistic studies and drug discovery [86]. …”

Section: Future Directionsmentioning

confidence: 99%

Risk factors in autism: Thinking outside the brain

Matelski

Water

2016

Journal of Autoimmunity

107

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Autism spectrum disorders (ASD) are complex neurodevelopmental conditions that have been rising markedly in prevalence for the past 30 years, now thought to affect 1 in 68 in the United States. This has prompted the search for possible explanations, and has even resulted in some controversy regarding the “true” prevalence of autism. ASD are influenced by a variety of genetic, environmental, and possibly immunological factors that act during critical periods to alter key developmental processes. This can affect multiple systems and manifests as the social and behavioral deficits that define these disorders. The interaction of environmental exposures in the context of an individual’s genetic susceptibilities manifests differently in each case, leading to heterogeneous phenotypes and varied comorbid symptoms within the disorder. This has also made it very difficult to elucidate underlying genes and exposure profiles, but progress is being made in this area. Some pharmaceutical drugs, toxicants, and metabolic and nutritional factors have been identified in epidemiological studies as increasing autism risk, especially during the prenatal period. Immunologic risk factors, including maternal infection during pregnancy, autoantibodies to fetal brain proteins, and familial autoimmune disease, have consistently been observed across multiple studies, as have immune abnormalities in individuals with ASD. Mechanistic research using animal models and patient-derived stem cells will help researchers to understand the complex etiology of these neurodevelopmental disorders, which will lead to more effective therapies and preventative strategies. Proposed therapies that need more investigation include special diets, probiotics, immune modulation, oxytocin, and personalized pharmacogenomic targets. The ongoing search for biomarkers and better treatments will result in earlier identification of ASD and provide much needed help and relief for afflicted families.

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“…The reprogramming and differentiation of iPSCs into neural progenitor cells (NPCs) and mature neurons is achieved by forced expression or exogenous addition of growth factors and small molecules (reviewed by Kim et al, 2014). The obtained cells are thought to undergo the neuronal developmental pathways observed in the brain, and can be easily cultured and stored (Song et al, 2013; Hu et al, 2010).…”

Section: Patient Biomaterials Models Advantages and Limitationsmentioning

confidence: 99%

Human dermal fibroblasts in psychiatry research

et al. 2016

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Summary In order to decipher the disease etiology, progression and treatment of multifactorial human brain diseases we utilize a host of different experimental models. Recently, patient-derived human dermal fibroblast (HDF) cultures have re-emerged as promising in vitro functional system for examining various cellular, molecular, metabolic and (patho)physiological states and traits of psychiatric disorders. HDF studies serve as a powerful complement to postmortem and animal studies, and often appear to be informative about the altered homeostasis in neural tissue. Studies of HDFs from patients with schizophrenia, depression, bipolar disorder, autism, attention deficit and hyperactivity disorder and other psychiatric disorders have significantly advanced our understanding of these devastating diseases. These reports unequivocally prove that signal transduction, redox homeostasis, circadian rhythms and gene*environment interactions are all amenable for assessment by the HDF model. Furthermore, the reported findings suggest that this underutilized patient biomaterial, combined with modern molecular biology techniques, may have both diagnostic and prognostic value, including prediction of response to therapeutic agents.

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Optimizing neuronal differentiation from induced pluripotent stem cells to model ASD

Cited by 52 publications

References 133 publications

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

Risk factors in autism: Thinking outside the brain

Human dermal fibroblasts in psychiatry research

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