iPSC-modelling reveals genetic associations and morphological alterations of oligodendrocytes in schizophrenia.

Abstract

There is strong evidence for a genetically driven neuronal contribution in schizophrenia (SCZ). Although imaging and postmortem studies also provide evidence for white matter alterations with implications of the oligodendroglial lineage in SCZ, it is unclear whether these disturbances are a secondary consequence of neuronal deficits or also, at least in parts, genetically driven and cell-autonomous. Using human induced pluripotent stem cells (hiPSCs) in combination with gene set enrichment analysis, we investigated the cellular impact of SCZ genetics on the oligodendroglial lineage. We performed unsupervised clustering analysis of hiPSC-differentiated neural cells including oligodendrocytes (iOLs) and their precursor cells (iOPCs) with corresponding human postmortem cell types from single-cell RNA sequencing (scRNAseq) data and conducted a comparative gene set enrichment analysis. Subsequently, we stratified individuals based on white matter alteration using diffusion tensor imaging (DTI) within a translational cohort (N = 112) and then explored the cellular effects of SCZ risk with hiPSC modelling in a subset of SCZ patients (N = 8) with disturbed white matter integrity and unaffected healthy controls (N = 7). hiPSC-iOPCs/iOLs expression profiles strongly correlated with human postmortem OPCs/OLs based on scRNAseq, and their transcriptional signatures were highly enriched in the genetic associations of SCZ. The cellular assessment of patient-derived iOPCs/iOLs revealed morphological alterations, including significantly increased branch length and elevated junction number in mature iOLs from SCZ. Moreover, transcriptomic profiling revealed a dysregulation in oligodendroglial cell signaling and proliferation. In sum, hiPSC-modelling shows an impact of SCZ genetics on dedicated features of the oligodendroglial lineage.