Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

TY - JOUR

T1 - Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

AU - Windrem, Martha S.

AU - Osipovitch, Mikhail

AU - Liu, Zhengshan

AU - Bates, Janna

AU - Chandler-Militello, Devin

AU - Zou, Lisa

AU - Munir, Jared

AU - Schanz, Steven

AU - McCoy, Katherine

AU - Miller, Robert H

AU - Wang, Su

AU - Nedergaard, Maiken

AU - Findling, Robert L.

AU - Tesar, Paul J.

AU - Goldman, Steven A.

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/8/3

Y1 - 2017/8/3

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.stem.2017.06.012

DO - 10.1016/j.stem.2017.06.012

M3 - Journal article

C2 - 28736215

SN - 1934-5909

VL - 21

SP - 195-208.e6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -