@article{76093dcb6bec4bdf82831761a279c026,
title = "Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia",
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",
author = "Windrem, {Martha S.} and Mikhail Osipovitch and Zhengshan Liu and Janna Bates and Devin Chandler-Militello and Lisa Zou and Jared Munir and Steven Schanz and Katherine McCoy and Miller, {Robert H.} and Su Wang and Maiken Nedergaard and Findling, {Robert L.} and Tesar, {Paul J.} and Goldman, {Steven A.}",
note = "Funding Information: This work was supported by NIMH grants R01MH099578 and R01MH104701, NINDS R01NS75345, the G. Harold and Leila Y. Mathers Charitable Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Novo Nordisk Foundation. We thank Alexis Yagielski and Simrat Dhaliwal for histological assistance, Jennifer Wintermute for assistance with cell culture, Lorenz Studer (Memorial Sloan Kettering) for the C27 hiPSC cell line, Nora McNamara (Case Western) for assistance with patient identification, Leslie Cooperman and Elizabeth Shick (Case Western) for assistance with producing the iPSC lines, and Chiara Cirelli (University of Wisconsin) for her comments on our sleep and activity data. This paper is dedicated to the memory of Mr. James T. Handelman of the Mathers Charitable Foundation, whose early and ardent support made this work possible. Drs. Goldman and Windrem hold a patent on human glial chimeric mice, US 7,524,491, from which they receive no financial remuneration. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = aug,
day = "3",
doi = "10.1016/j.stem.2017.06.012",
language = "English (US)",
volume = "21",
pages = "195--208.e6",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "2",
}