Neural Stem Cells in the Subventricular Zone Are a Source of Astrocytes and Oligodendrocytes, but Not Microglia

Abstract

The developmental origin of microglia remains a controversial subject. While it is generally accepted that primitive fetal macrophages that migrate from the yolk sac to the brain become microglia, it also has been argued that there is a second source of microglia that are of neuroectodermal lineage. To determine whether progenitors in the dorsolateral subventricular zone (SVZ_DL) are capable of producing microglia as well as macroglia, we infected perinatal rat SVZ_DL cells with a mixture of two replication-deficient retroviruses, placed these progenitors in vitro and then varied the media formulations to promote microglial differentiation. Mixed macroglial clones were obtained, but no heterogeneous clones containing microglia were observed, regardless of the media components. Among the macroglial clones, we observed every possible combination of type 1 astrocyte and O-2A lineage cells. Some clones were homogeneous and contained cells belonging to a single macroglial lineage. Other clonal clusters were heterogeneous and were comprised of type 1 astrocytes and oligodendrocytes, type 1 and type 2 astrocytes, or type 2 astrocytes and oligodendrocytes. Of 130 clones examined, where we used triple immunofluorescence with antibodies that recognize microglia, 2 clonal clusters contained OX-42+ microglia that were retrovirally labeled, but all of the cells in those clones expressed the microglial marker and none expressed either GFAP or O4. In addition, we isolated neural stem cells from the perinatal SVZ_DL and assessed their capacity to generate macroglia and microglia. Confirming and extending our previous analyses, neural stem cells generated homogeneous and heterogeneous macroglial clones, but they did not generate microglia. We conclude that brain macroglia and microglia do not share a common precursor, even though the neural stem cells in the SVZ_DL cells can produce neurons, astrocytes and oligodendrocytes. Therefore, the microglia that reside in the SVZ_DL are immigrants from nonneural precursors.

Glial activation in white matter following ischemia in the neonatal P7 rat brain

“…At this time point of recovery, Ki-67 labeling was seen in the deeper cortical layer surrounding the infarct and in white matter tracts, suggesting migration of newly generated cells from dorsolateral SVZ toward lesioned cortex and white matter. Most of the Ki-67-positive nuclei represent proliferative NG2-positive pro-OLs and astrocytes during the first week of recovery in response neonatal stroke, as previously reported following HI (Levison et al, 2003). Upregulation of NG2 expression has also been observed following ischemia-reperfusion in adult rat (Tanaka et al, 2003).…”

Astrocytic Demise in the Developing Rat and Human Brain after Hypoxic-Ischemic Damage

“…necrotic features after ischemia [41] . It is also interesting to note that perinatal HI damages and depletes (with caspase-3 activation) progenitors, the source of astrocytes and oligodendrocytes [46] , from the subventricular zone [47] .…”

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

“…Using cell genesis and fate specifying processes, neural tube-derived neural stem cells give rise to 10 11 neurons and at least 10 12 glial cells of many different phenotypes in the adult brain [47][48][49] . Neural stem cells (NSCs) are an attractive source for generating astroglial cells through their multipotency and high potential of self-renewal.…”