Early microglial colonization of the human forebrain and possible involvement in periventricular white‐matter injury of preterm infants

Abstract

Amoeboid microglial subpopulations visualized by antibodies against ionized calcium-binding adapter molecule 1, CD68, and CD45 enter the forebrain starting at 4.5 postovulatory or gestational weeks (gw). They penetrate the telencephalon and diencephalon via the meninges, choroid plexus, and ventricular zone. Early colonization by amoeboid microglia-macrophages is first restricted to the white matter, where these cells migrate and accumulate in patches at the junctions of white-matter pathways, such as the three junctions that the internal capsule makes with the thalamocortical projection, external capsule and cerebral peduncle, respectively. In the cerebral cortex anlage, migration is mainly radial and tangential towards the immature white matter, subplate layer, and cortical plate, whereas pial cells populate the prospective layer I. A second wave of microglial cells penetrates the brain via the vascular route at about 12-13 gw and remains confined to the white matter. Two main findings deserve emphasis. First, microglia accumulate at 10-12 gw at the cortical plate-subplate junction, where the first synapses are detected. Second, microglia accumulate in restricted laminar bands, most notably around 19-30 gw, at the axonal crossroads in the white matter (semiovale centre) rostrally, extending caudally in the immature white matter to the visual radiations. This accumulation of proliferating microglia is 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 such as axonal guidance, synaptogenesis, and neurodevelopmental apoptosis as well as in injuries to the developing brain, in particular in the periventricular white-matter injury of preterm infants.

Microglia activation in the extremely preterm human brain

“…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).…”

“…It was proposed that the normal developmental increase in resident microglia renders the human neonatal periventricular white matter (PVWM) more susceptible to injury (6,8,14,15). The PVWM regions are the most frequent site of preterm white matter injuries, such as periventricular leukomalacia, punctate lesions, and diffuse excessive high signal intensity, which are evident on magnetic resonance imaging (MRI).…”

“…Premyelinating oligodendrocytes in the developing brain are particularly vulnerable to oxidative and excitotoxic stress (4,5), and activated microglia are thought to contribute to this (6). Microglia, the resident phagocytic cells of the central nervous system (7), take on a ramified quiescent morphology in the normal mature brain, but the active forms of intermediate and amoeboid morphologies are most common in normal developing brain (8). Activated microglia in the developing white matter are involved in eliminating transcallosal projections (9), vascularization and angiogenesis (7), myelination (10), programmed cell death, synaptic pruning (11), and axonal guidance (12).…”

Brain Barriers and a Subpopulation of Astroglial Progenitors of Developing Human Forebrain Are Immunostained for the Glycoprotein YKL-40

“…Early colonization is initially restricted to the IZ. A second wave of monocytes penetrates into the brain via the vascular route at about 12 wpc and remains confined to the IZ/white matter (Verney et al 2010). Areas known to harbor microglia are the inner SVZ, SP, lower cortical plate and restricted laminar bands at the axonal crossroads in the white matter (Rezaie et al 2005;Verney et al 2010;Cunningham et al 2013).…”