Localization of morphologically distinct microglial populations in the developing human fetal brain: implications for ontogeny

Although 70 years have elapsed since del Rio Hortega's initial description of microglia, the ontogeny of these cells remains enigmatic. In addition to the general scientific importance of clarifying this issue, a more complete characterization of microglia is dictated by their apparent pivotal role in the pathophysiology of central nervous system (CNS) disease associated with the acquired immunodeficiency syndrome (AIDS) in adults and, especially, in children. To accomplish this goal, fetal central nervous system tissue was collected at the time of elective pregnancy terminations. Coronal vibratome sections of Bouin's-fixed cerebrum were either stained with Ricinus communis agglutinin-1 (RCA-1) or analyzed by immunohistochemistry using monoclonal antibodies that recognize human tissue macrophages and microglia. By at least 13 weeks of gestation, microglia were detected in fetal brain. In the 13-18 week gestational age cerebrum, there was variability in the morphology of microglia within the developing white matter and cortex. However, there was less variability within these areas in the 19-24 week gestational age group. At all ages the greatest number of labeled cells per field was in the germinal matrix with decreasing numbers in the developing white matter and cortex. Cells in the germinal matrix were round with short processes ('ameboid microglia') while cortical cells were more ramified ('resting microglia'). These results suggest that microglia may originate in the germinal matrix rather than in the pial mesenchyme as originally hypothesized by del Rio Hortega. Furthermore, because microglia may be the major cellular target for HIV-1 infection in the fetus, if they are not present in human fetal CNS prior to 13 weeks gestation then HIV-1 CNS infection would seem less likely prior to this age. Elucidation of these points might lead to improved preventative or therapeutic strategies in the treatment of perinatal and pediatric AIDS.