Neonatal engraftment by oligodendrocyte progenitor cells (OPCs) permits the myelination of congenitally dysmyelinated brain. To establish a potential autologous source of these cells, we developed a strategy by which to differentiate human induced pluripotential stem cells (hiPSCs) into OPCs. From 3 hiPSC lines, as well as from human embryonic stem cells (hESCs), we generated highly enriched OLIG2+/PDGFRα+/NKX2.2+/SOX10+ hOPCs, which could be further purified using fluorescence-activated cell sorting. hiPSC OPCs efficiently differentiated into both myelinogenic oligodendrocytes and astrocytes, in vitro and in vivo. Neonatally engrafted hiPSC OPCs robustly myelinated the brains of myelin-deficient shiverer mice, and substantially increased the survival of these mice. The speed and efficiency of myelination by hiPSC OPCs was higher than that previously observed using fetal tissue-derived OPCs, and no tumors from these grafts were noted as long as 9 months after transplant. These results suggest the utility of hiPSC-derived OPCs in treating disorders of myelin loss.

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. RNAseq of cultured SCZ 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.

Astrocytic differentiation is developmentally impaired in patients with childhood-onset schizophrenia (SCZ). To determine why, we used genetic gain- and loss-of-function studies to establish the contributions of differentially-expressed transcriptional regulators to the defective differentiation of glial progenitor cells (GPCs) produced from SCZ patient-derived iPSCs. Negative regulators of the BMP pathway were upregulated in SCZ GPCs, including BAMBI, FST and GREM1, whose over-expression retained SCZ GPCs at the progenitor stage. SMAD4 knock-down suppressed the production of these BMP inhibitors by SCZ GPCs, and rescued normal astrocytic differentiation. In addition, the BMP-regulated transcriptional repressor REST was upregulated in SCZ GPCs, and its knock-down similarly restored normal glial differentiation. REST knockdown also rescued potassium-transport associated gene expression and K+ uptake, which were otherwise deficient in SCZ glia. These data suggest that the glial differentiation defect in childhood-onset SCZ, and its attendant disruption in K+ homeostasis, may be rescued by targeting BMP/SMAD4- and REST-dependent transcription.