Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals.

Autor: Adhya D; Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Swarup V; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California., Nagy R; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Dutan L; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Shum C; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Valencia-Alarcón EP; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Jozwik KM; Cancer Research UK Cambridge Institute, Cambridge, United Kingdom., Mendez MA; Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Horder J; Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Loth E; Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Nowosiad P; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Lee I; Behavioural and Brain Sciences Unit, Population Policy Practice Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom., Skuse D; Behavioural and Brain Sciences Unit, Population Policy Practice Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom., Flinter FA; Department of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom., Murphy D; Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., McAlonan G; Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom., Geschwind DH; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California; Department of Human Genetics, University of California, Los Angeles, Los Angeles, California., Price J; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom., Carroll J; Cancer Research UK Cambridge Institute, Cambridge, United Kingdom., Srivastava DP; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom. Electronic address: deepak.srivastava@kcl.ac.uk., Baron-Cohen S; Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
Jazyk: angličtina
Zdroj: Biological psychiatry [Biol Psychiatry] 2021 Mar 01; Vol. 89 (5), pp. 486-496. Date of Electronic Publication: 2020 Jun 23.
DOI: 10.1016/j.biopsych.2020.06.014
Abstrakt: Background: Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.
Methods: iPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation.
Results: A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.
Conclusions: Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.
(Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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