Abstract
Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P=2.66 × 10−10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P=3.07 × 10−19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the central nervous system. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter and cytoskeletal signalling occurs during early fetal brain development of BD I patients.
Highlights
Bipolar disorder (BD) is a severe and chronic disorder characterised by the cyclic occurrence of episodes of mania and depression
After expansion in our laboratory, presence of pluripotency markers Oct[4], SSEA4 and sialy-lactotetra (TR4)[39] was confirmed by immunofluorescence (Figure 1a). These results demonstrate the successful generation of pluripotent induced pluripotent stem cell (iPSC) lines from BD patients and healthy controls
NLRP2 is the most significant differentially expressed gene (DEG), at both the iPSC and neural stem cell (NSC) stages, in discriminating BD from healthy controls To identify BD-associated genes, we examined the average differences in gene expression in samples from BD I patients relative to the healthy control iPSC and NSC cell lines, respectively
Summary
Bipolar disorder (BD) is a severe and chronic disorder characterised by the cyclic occurrence of episodes of mania and depression. There is a need to investigate the global transcriptome of BD I patients and healthy controls during the early stages of neural development, that is, the neural stem cell (NSC) stage For this purpose, we used disease modelling using iPSC plates and maintained in neural maintenance media. To ensure that the samples were not observed, and both iPSC and neuro-epithelial cells were frozen in RNA contaminated with genomic DNA, an additional DNase I digestion step was protect (Qiagen, Redwood City, CA, USA) for miRNA and transcriptome performed with RNase-free DNase (Norgen) according to the manufacanalysis. Analysis of DEGs was performed using DESeq[2] between iPSC and NSC stages for BD and control cell lines, respectively.
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