Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction
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REVIEW
Human stem cell‑based models for studying autism spectrum disorder‑related neuronal dysfunction Arquimedes Cheffer1†, Lea Jessica Flitsch1† , Tamara Krutenko1, Pascal Röderer2, Liubov Sokhranyaeva3, Vira Iefremova1, Mohamad Hajo1, Michael Peitz1,2,4 , Martin Karl Schwarz2,3 and Oliver Brüstle1*
Abstract The controlled differentiation of pluripotent stem cells (PSCs) into neurons and glia offers a unique opportunity to study early stages of human central nervous system development under controlled conditions in vitro. With the advent of cell reprogramming and the possibility to generate induced pluripotent stem cells (iPSCs) from any individual in a scalable manner, these studies can be extended to a disease- and patient-specific level. Autism spectrum disorder (ASD) is considered a neurodevelopmental disorder, with substantial evidence pointing to early alterations in neurogenesis and network formation as key pathogenic drivers. For that reason, ASD represents an ideal candidate for stem cell-based disease modeling. Here, we provide a concise review on recent advances in the field of human iPSC-based modeling of syndromic and non-syndromic forms of ASD, with a particular focus on studies addressing neuronal dysfunction and altered connectivity. We further discuss recent efforts to translate stem cell-based disease modeling to 3D via brain organoid and cell transplantation approaches, which enable the investigation of disease mechanisms in a tissue-like context. Finally, we describe advanced tools facilitating the assessment of altered neuronal function, comment on the relevance of iPSC-based models for the assessment of pharmaceutical therapies and outline potential future routes in stem cell-based ASD research. Keywords: Autism spectrum disorder, Induced pluripotent stem cells, Cell reprogramming, Brain organoids, Neuronal connectivity, In vitro differentiation Introduction According to the 5th edition of the ‘Diagnostic and Statistical Manual of Mental Disorders’, autism is a developmental disorder with impairments in social interaction and communication, which is characterized by restricted and repetitive behavior patterns [1]. Autism has an average worldwide prevalence of 0.6–1%. In about 5% of all *Correspondence: brustle@uni‑bonn.de † Arquimedes Cheffer and Lea Jessica Flitsch contributed equally to this work 1 Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty & University Hospital Bonn, Venusberg‑Campus 1, Building 76, 53127 Bonn, Germany Full list of author information is available at the end of the article
cases, it is associated with syndromic forms of ASD such as fragile X syndrome (FXS; FMR1 mutation), Rett syndrome (RTS; MECP2 mutation), Angelman syndrome (15q11q13 deletion), Timothy syndrome (CACNA1C mutation), Phelan-McDermid syndrome (22q13 deletion) and Kleefstra syndrome (EHMT1 mutation) [2]. Furthermore, there are several other genetic conditions, which are less stringently correlated to autism (reviewed in detail by [3]). Interestingly, genes
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