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Cell Stem Cell. 2017 Aug 3;21(2):195-208.e6. doi: 10.1016/j.stem.2017.06.012. Epub 2017 Jul 20.

Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.

Author information

1
Department of Neurology and Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
2
Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark.
3
Department of Neuroscience, George Washington University School of Medicine, Washington, D.C. 20037, USA.
4
Department of Neurology and Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark.
5
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Department of Genetics, Case Western University Medical School, Cleveland, OH 44106, USA.
7
Department of Neurology and Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, 2200 Copenhagen N, Denmark; Neuroscience Center, Rigshospitalet, 2100 Copenhagen, Denmark. Electronic address: steven_goldman@urmc.rochester.edu.

Abstract

In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.

KEYWORDS:

astrocyte; childhood-onset schizophrenia; dysmyelination; glia; glial differentiation; iPSC; induced pluripotent stem cell; mouse models; myelin; schizophrenia

PMID:
28736215
PMCID:
PMC5576346
DOI:
10.1016/j.stem.2017.06.012
[Indexed for MEDLINE]
Free PMC Article

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