Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia
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Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. / Windrem, Martha S.; Osipovitch, Mikhail; Liu, Zhengshan; Bates, Janna; Chandler-Militello, Devin; Zou, Lisa; Munir, Jared; Schanz, Steven; McCoy, Katherine; Miller, Robert H; Wang, Su; Nedergaard, Maiken; Findling, Robert L.; Tesar, Paul J.; Goldman, Steven A.
In: Cell Stem Cell, Vol. 21, No. 2, 03.08.2017, p. 195-208.e6.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 21
SP - 195-208.e6
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 2
ER -
ID: 185945824