Spatiotemporal dynamics of human microglia are linked with brain developmental processes across the lifespan

Abstract

SUMMARYMicroglia, the brain’s resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97 postmortem tissues enabling quantitative, sex-matched, detailed analysis of microglial across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides unparalleled insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Rubella virus tropism and single cell responses in human primary tissue and microglia-containing organoids

“…Such specificity of RV for microglia in this model is striking given that microglia represent only 1-5% of the cells of the human developing brain (D.A. Menassa et al, 2021). Moreover, the previously published viral entry factor MOG is not specific to microglia according to analysis of publicly available RNA and protein expression profiles of the human developing brain (Supplementary Figure 2).…”

Microglial Characterization in Transient Human Neurodevelopmental Structures

“…Microglia are mesoderm-derived glial cells that begin colonizing the brain rudiment from the 4th pcw at the very onset of many morphogenetic and neurogenetic events [12,13]. The extent to which these cells participate in developmental events is known from rodents: microglia are required for guiding interneurons to their correct position in the cortex and the refinement of dopaminergic axons [14]; microglia restrict the progenitor pool by the phagocytosis of neuronal precursors [15] and prune supernumerary synapses [16].…”

“…In human development, ascribed microglial roles include the clearance of apoptotic cells in the telencephalon [17], the formation of white matter tracts such as the corpus callosum [18], and the tracking of migrating neurons in the frontal lobe [19]. Microglial spatiotemporal dynamics undulate within critical windows during early fetal, midfetal, and early postnatal life in the telencephalon [13]. These undulations are associated with the appearance of transient structures such as the cortical plate and the subplate.…”

“…Microglial morphology varies by the transient layer during brain development. We have previously documented the variability in morphologies observed in the telencephalic wall [13]. Microglia tend to be amoeboid when they arrive to the brain rudiment, develop a leading process to migrate tangentially or radially (to the pial surface) to reach their final destination, develop a prolifera-tive core to expand the population size, or karyolyse to die in order to refine the population [13].…”

“…We have previously documented the variability in morphologies observed in the telencephalic wall [13]. Microglia tend to be amoeboid when they arrive to the brain rudiment, develop a leading process to migrate tangentially or radially (to the pial surface) to reach their final destination, develop a prolifera-tive core to expand the population size, or karyolyse to die in order to refine the population [13]. Phagocytic microglia develop pouches in their processes or at a late stage of phagocytosis are sizeable and amoeboid [20].…”