Title | Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, Munir J, Schanz S, McCoy K, Miller RH, Wang S, Nedergaard M, Findling RL, Tesar PJ, Goldman SA |
Journal | Cell Stem Cell |
Volume | 21 |
Issue | 2 |
Pagination | 195-208.e6 |
Date Published | 2017 Aug 03 |
ISSN | 1875-9777 |
Keywords | Animals, Astrocytes, Behavior, Cell Differentiation, Chimera, Gene Expression Regulation, Humans, Induced Pluripotent Stem Cells, Mice, Myelin Sheath, Neuroglia, Phenotype, 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. |
DOI | 10.1016/j.stem.2017.06.012 |
Alternate Journal | Cell Stem Cell |
PubMed ID | 28736215 |
PubMed Central ID | PMC5576346 |
Grant List | R01 AG048769 / AG / NIA NIH HHS / United States R01 NS078304 / NS / NINDS NIH HHS / United States R01 MH104701 / MH / NIMH NIH HHS / United States R01 NS075345 / NS / NINDS NIH HHS / United States R01 MH099578 / MH / NIMH NIH HHS / United States R01 NS100366 / NS / NINDS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm