Abstract
Microglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in the annotation of candidate biomarkers, we conducted a meta-analysis of brain cells using available high-throughput data sets for deciphering microglia-specific expression profiles. We have identified 3,290 significant genes specific to microglia and further selected the top 20 dysregulated genes on the basis of p-value and log2FC. To this list, we added 7 known microglia-specific markers making the candidate list comprising 27 genes for further downstream analyses. Next, we established a connectome of these potential markers with their putative protein partners, which demonstrated strong associations of upregulated genes like Dedicator of cytokinesis 2 (DOCK2) with early/mature microglial markers such as Sphingosine kinase 1 (SPHK1), CD68, and CD45. To elucidate their respective brain anatomical location, we deconvoluted the BrainSpan Atlas expression data. This analysis showed high expression of the majority of candidate genes in microglia-dense regions (Amygdala, Hippocampus, Striatum) in the postnatal brain. Furthermore, to decipher their localized expression across brain ages, we constructed a developmental dynamics map (DDM) comprising extensive gene expression profiles throughout prenatal to postnatal stages, which resulted in the discovery of novel microglia-specific gene signatures. One of the interesting readout from DDM is that all the microglia-dense regions exhibit dynamic regulation of few genes at 37 post conception week (pcw), the transition period between pre- and postnatal stages. To validate these findings and correlate them as potential biomarkers, we analyzed the expression of corresponding proteins in hESC-derived human microglia precursors. The cultured microglial precursors showed expression of Pentraxin 3 (PTX3) and SPHK1 as well as several known markers like CD68, Allograft inflammatory factor 1 (AIF1/IBA1). In summary, this study has furnished critical insights into microglia dynamics across human brain ages and cataloged potential transcriptomic fingerprints that can be further exploited for designing novel neurotherapeutics.
Highlights
IntroductionThe complex human brain is composed of neurons embedded in a framework of glial cells (astrocytes, oligodendrocytes, and microglia) and blood vessels
The complex human brain is composed of neurons embedded in a framework of glial cells and blood vessels
The samples of various cellular origins were tested for homogeneity via 2D-Principal Component Analysis which resulted in noticeable differences in microglia sample cluster from other cell types in Principal components, PC 1 and PC 2 (Figure 2B)
Summary
The complex human brain is composed of neurons embedded in a framework of glial cells (astrocytes, oligodendrocytes, and microglia) and blood vessels. Microglia control the number of NPCs by selectively colonizing near proliferative NPC zones and phagocytizing the neural precursors in utero, and second, the microglial activity gets regulated in the brain by NPC-derived chemokines, such as VEGF, as shown by increased microglial density surrounding NPC pool [9, 10]. This NPC-microglia crosstalk is most active during neuroinflammation, as microglia is one of the primary innate immunoeffector cells [10, 11]. Albeit monumental efforts made toward understanding microglia dynamics in the developing brain, knowledge regarding their cellular localization, self-renewal/expansion property, and other stage-specific roles is still in its infancy
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