Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

Dwaipayan Adhya; Vivek Swarup; Roland Nagy; Lucia Dutan; Carole Shum; Eva P Valencia-Alarcón; Kamila Maria Jozwik; Maria Andreina Mendez; Jamie Horder; Eva Loth; Paulina Nowosiad; Irene Lee; David Skuse; Frances A Flinter; Declan Murphy; Grainne McAlonan; Daniel H Geschwind; Jack Price; Jason Carroll; Deepak P Srivastava; Simon Baron-Cohen

doi:10.1016/j.biopsych.2020.06.014

Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

Biol Psychiatry. 2021 Mar 1;89(5):486-496. doi: 10.1016/j.biopsych.2020.06.014. Epub 2020 Jun 23.

Authors

Dwaipayan Adhya¹, Vivek Swarup², Roland Nagy³, Lucia Dutan³, Carole Shum³, Eva P Valencia-Alarcón³, Kamila Maria Jozwik⁴, Maria Andreina Mendez⁵, Jamie Horder⁵, Eva Loth⁵, Paulina Nowosiad³, Irene Lee⁶, David Skuse⁶, Frances A Flinter⁷, Declan Murphy⁵, Grainne McAlonan⁵, Daniel H Geschwind⁸, Jack Price⁹, Jason Carroll⁴, Deepak P Srivastava¹⁰, Simon Baron-Cohen¹¹

Affiliations

¹ 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.
² Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California.
³ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁴ Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
⁵ Department of Forensic and Neurodevelopmental Sciences, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁶ Behavioural and Brain Sciences Unit, Population Policy Practice Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
⁷ Department of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.

Abstract

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.

Keywords: Autism; Cortical differentiation; Functional genomics; Midbrain differentiation; Neural precursors; Neural progenitor cells; Neurodevelopment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autistic Disorder*
Cell Differentiation
Female
Humans
Induced Pluripotent Stem Cells*
Neurogenesis
Neurons
Pregnancy

Abstract

Publication types

MeSH terms

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