Abstract
Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG cells developed typical microglial ramified morphology, expressed microglial specific surface markers (P2RY12 and TMEM119), and possessed phagocytic activity. Principal component analyses and multidimensional scaling analyses of RNA-seq data showed that iMG cells were distinct from monocytes and induced macrophages (iMacs) but clustered closer to human microglia and hiPSC-induced microglia. Heatmap analyses also found that iMG cells, but not monocytes, were closely clustered with human primary microglia. Further pathway and relative expression analysis indicated that unique genes from iMG cells were involved in the regulation of the complement system, especially in the synapse and ion transport. Overall, our data demonstrated that the iMG model mimicked many features of the brain resident microglia, highlighting its utility in the study of microglial function in many brain diseases, such as schizophrenia and Alzheimer's disease (AD).
Highlights
Microglia are the primary immune cells of the central nervous system (CNS) that belong to the myeloid lineage
In vitro differentiation from human induced pluripotent stem cell (hiPSC) to microglia is challenging as the reprogramming process is time-consuming (Liang and Zhang, 2013)
Consistent with the previous studies (Ohgidani et al, 2014; Sellgren et al, 2017), our data showed that iMG cells had the typical ramified morphology as resting microglia in the brain and expressed microglia-specific surface markers, such as transmembrane protein 119 (TMEM119) and P2RY12
Summary
Microglia are the primary immune cells of the central nervous system (CNS) that belong to the myeloid lineage. A similar pattern of events may occur in humans, but under certain inflammatory conditions, the recruitment of bone marrow-derived progenitors may supplement the microglial population to some extent (Ginhoux and Prinz, 2015). The origins of human microglia are more heterogeneous, with one population from myeloid/mesenchymal origin in the yolk sac and a second population representing a developmental and transitory form of fetal macrophage (possibly monocytes). Microglia proliferate and self-renew continually throughout life to maintain cell numbers, without any contribution from bone marrow-derived macrophages (Elmore et al, 2014). Microglia serve a variety of important functions, including immune surveillance, neurogenesis, synaptic pruning, and phagocytosis (Stansley et al, 2012). Microglia-mediated synaptic loss by phagocytosis strongly correlates with cognitive decline in patients with schizophrenia or AD
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