ABSTRACT
Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
Subject(s)
Autism Spectrum Disorder , Induced Pluripotent Stem Cells , Autism Spectrum Disorder/genetics , Humans , Neurons , Proteomics , Transcriptome/geneticsSubject(s)
Autism Spectrum Disorder/pathology , Gene Expression Regulation/physiology , Multipotent Stem Cells/metabolism , Multiprotein Complexes/metabolism , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Androstadienes/pharmacology , Case-Control Studies , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Child , Culture Media, Serum-Free/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Humans , Immunosuppressive Agents/pharmacology , Male , Mechanistic Target of Rapamycin Complex 1 , Multipotent Stem Cells/drug effects , Phosphorylation/drug effects , Serum/metabolism , Signal Transduction/drug effects , Sirolimus/pharmacology , Time Factors , WortmanninABSTRACT
Gingival overgrowth is a common side-effect of administration of the immunosuppressant cyclosporin A and the anti-epileptic drug phenytoin. While cyclosporin-induced gingival overgrowth is often accompanied by gingival inflammation, phenytoin-induced gingival overgrowth usually forms fibrotic lesions. To determine whether these drugs alter the inflammatory responses of gingival fibroblasts, we investigated the effects of cyclosporin and phenytoin on Toll-like receptor (TLR)-mediated responses to microbial components. In Chinese hamster ovary reporter cell lines, cyclosporin alone triggered signaling, whereas phenytoin down-regulated signaling induced by the TLR2 or TLR4 ligand. In human gingival fibroblasts, cyclosporin alone did not induce evident inflammatory responses, but augmented the expression of CD54 and the production of interleukin (IL)-6 and IL-8 induced by TLR ligands, whereas phenytoin attenuated those responses. Cyclosporin also augmented CD54 expression in gingiva of mice injected with lipopolysaccharide. These results indicated that cyclosporin positively and phenytoin negatively modulated inflammatory responses of human gingival fibroblasts.
