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Review
. 2018 Aug 23;9(1):226.
doi: 10.1186/s13287-018-0966-2.

Induced Pluripotent Stem Cells as a Tool to Study Brain Circuits in Autism-Related Disorders

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Free PMC article
Review

Induced Pluripotent Stem Cells as a Tool to Study Brain Circuits in Autism-Related Disorders

Aline Vitrac et al. Stem Cell Res Ther. .
Free PMC article

Abstract

The mammalian brain is a very complex organ containing an estimated 200 billion cells in humans. Therefore, studying human brain development has become very challenging given all the data that are available from different approaches, notably genetic studies.Recent pluripotent stem cell methods have given rise to the possibility of modeling neurodevelopmental diseases associated with genetic defects. Fibroblasts from patients have been reprogrammed into pluripotent stem cells to derive appropriate neuronal lineages. They specifically include different subtypes of cortical neurons that are at the core of human-specific cognitive abilities. The use of neurons derived from induced pluripotent stem cells (iPSC) has led to deciphering convergent and pleiotropic neuronal synaptic phenotypes found in neurodevelopmental disorders such as autism spectrum disorders (ASD) and their associated syndromes. In addition to these initial studies, remarkable progress has been made in the field of stem cells, with the major objective of reproducing the in vivo maturation steps of human neurons. Recently, several studies have demonstrated the ability of human progenitors to respond to guidance cues and signals in vivo that can direct neurons to their appropriate sites of differentiation where they become fully mature neurons.We provide a brief overview on research using human iPSC in ASD and associated syndromes and on the current understanding of new theories using the re-implantation of neural precursors in mouse brain.

Keywords: Autism; Brain circuits; Developmental disorders; Human induced pluripotent stem cells; Transplantation.

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The graphic figure in this article is original and is subject to the copyright policy of the journal.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Main experimental designs for human iPSC models of monogenic neurodevelopmental disorders. a Patient’s specific iPSC are derived from fibroblasts using the four Yamanaka’s factors. Genome engineering using the CRISPR/Cas9 method allows the reversion of phenotypic defects by re-introducing the wild-type allele into the genome of iPSC lines. The CRISPR/Cas9 method also allows introduction of the mutation under study directly into the genome of control iPSC lines in order to compare visually similar phenotypes to those seen in the iPSC from patients. Both non-edited and isogenic iPSC are differentiated into the affected neuronal subtypes, mostly pyramidal cortical neurons in the case of cognitive disorders. b Viable neurons can be maintained in culture up to 70 days after the differentiation of neural stem cells (NSC). The transduction of neuronal cells with a green fluorescent protein (GFP)-lentivirus allows their visualization and phenotypic characterization using fluorescence microscopy. A GFP-labeled pyramidal neuron 40-45 days after the differentiation of NSC. c Neuronal precursors or neurons fully differentiated in vitro are transplanted into the brain of mouse neonates. The visualization of fluorescent neurons is done using fluorescent microscopy on brain slices. A transplanted GFP-labeled pyramidal neuron is illustrated at 40–50 days post-injection (picture from our experiments). Mice are maintained up to 9 months of age after grafting. d Comparative information and main therapeutics perspectives provided by the use of iPSC-derived neurons in vitro vs in vivo

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