Unraveling the microglia-oligodendrocyte transcriptomic crosstalk for the identification of myelination biomarkers

Abstract

Background: While there is information on transcriptomic biomarkers of demyelination, the heterogeneity in the methods and cell types/tissues used makes it difficult to select transcriptomic biomarkers for demyelination studies. In addition, there is scarce data on the crosstalk between microglia and oligodendrocyte progenitor cells (OPCs), 2 of the 4 cell types involved in demyelination/remyelination processes. Objectives: To identify 1) transcriptomic biomarkers of demyelination in microglia, OPCs and corpus callosum following a similar pipeline, and 2) microglia ligands and OPC receptors and targets genes involved in the microglia-OPC crosstalk. Methods: Data were obtained from all available studies of gene expression data by microarray in mice samples treated with cuprizone available at GEO/Array Express. Differential expression analyses were performed to identify transcriptomic biomarkers. The following pipeline was used: quality control, normalization, annotation, gene filtering, aggregation, batch effect correction, differential expression analysis, annotation, plotting and functional analysis. The crosstalk analysis was performed with the NicheNet model for intercellular communication using expressed genes in microglia and OPCs obtained from the differential expression analysis. Ligand-target regulatory potentials, ligand receptor networks and ligand-receptor interactions were obtained from the NicheNet model. Analyses were performed in R. Results: There were 166, 12, and 2730 differential expressed genes (DEGs) identified in the corpus callosum, microglia and OPC differential expression analyses, respectively. DEGs included genes associated with demyelination such as Ninj2, Lpl, and Mobp. DEGs identified in the corpus callosum and OPC analyses were associated with GO terms and Wikipathways related to myelin. There was 1 DEG identified in both the microglia and the OPCs analyses, and 95 DEGs identified in both the corpus callosum and OPCs analyses. We identified 45 potential ligands of microglia that could affect gene expression in OPCs, 115 DEGs in OPCs that were predicted target genes of these ligands, and 43 potential OPC receptors of the identified microglia ligands. Some of the identified microglia ligands, and OPC receptors and targets genes, were differentially expressed in cuprizone treated samples compared to control and were associated with demyelination and myelin formation. Conclusions: The differential expression pipeline was able to identify transcriptomic biomarkers associated to demyelination in studies using different platforms and cell types/tissues. The crosstalk analysis between microglia and OPCs identified novel microglia ligands, and OPC receptors and target genes.