Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

Martha S. Windrem, Mikhail Osipovitch, Zhengshan Liu, Janna Bates, Devin Chandler-Militello, Lisa Zou, Jared Munir, Steven Schanz, Katherine McCoy, Robert H. Miller, Su Wang, Maiken Nedergaard, Robert L. Findling, Paul J. Tesar, Steven A. Goldman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)195-208.e6
JournalCell stem cell
Volume21
Issue number2
DOIs
StatePublished - Aug 3 2017

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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