Entry and Distribution of Microglial Cells in Human Embryonic and Fetal Cerebral Cortex

Abstract

Microglial cells penetrate into and scatter throughout the human cortical grey and white matter according to a specific spatiotemporal pattern during the first 2 trimesters of gestation. Routes of entry were quantitatively and qualitatively different from those identified in the diencephalon. Starting at 4.5 gestational weeks, amoeboid microglial cells, characterized by different antibodies as Iba1, CD68, CD45, and MHC-II, entered the cerebral wall from the ventricular lumen and the leptomeninges. Migration was mainly radial and tangential toward the immature white matter, subplate layer, and cortical plate, whereas pial cells populated the prospective layer I. The intraparenchymal vascular route of entry was detectable only from 12 gestational weeks. Interestingly, microglial cells accumulated in restricted laminar bands particularly at 19 to 24 gestational weeks among the corona radiata fibers rostrally, extending caudally in the immature white matter to reach the visual radiations. This accumulation of proliferating MIB1-positive microglia (as shown by MIB1-Iba1 double immunolabeling) was located at the site of white matter injury in premature neonates. The spatiotemporal organization of microglia in the immature white and grey matter suggests that these cells may play active roles in developmental processes and in injury to the developing brain.

Microglia activation in the extremely preterm human brain

“…The large numbers of microglia in the control PVWM as compared with other areas is consistent with previous studies (14,25,26), in which they were also mainly of amoeboid or intermediate active morphology. Microglia in the preterm PVWM were predominantly Iba1/CD68-immunopositive activated microglia.…”

“…Activated microglia in the first-trimester human brain preferentially express Iba1 and CD45 and are suggested to be of hematopoietic leukocyte origin (8,26,37). As microglia accumulate in these sites, they become more Iba1-and CD68-immunopositive (8,26,37). By 25-30 wk GA, Iba1-immunopositive resident microglia populations in the developing human brain were strongly CD68-immunopositive and only slightly CD45-immunopositive (40).…”

“…CD45 is expressed in nucleated hematopoietic cells and lymphocytes. Activated microglia in the first-trimester human brain preferentially express Iba1 and CD45 and are suggested to be of hematopoietic leukocyte origin (8,26,37). As microglia accumulate in these sites, they become more Iba1-and CD68-immunopositive (8,26,37).…”

“…All three antibodies are expressed in ramified and activated microglia (26,37). CD68 is also expressed in the lysosomal granules of macrophages in both the developing and adult brain (38,39) and is a marker of phagocytosis.…”

LPS-induced TLR4 neuroinflammatory signaling in CHME-5 microglial cells

“…Microglia are of monocytic lineage and take residence in the CNS during the first and second trimesters of embryonic development [22,23] . Much of what is known about microglial cells is derived from in vitro studies using primary or transformed cell lines of mouse or rat origin.…”