Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages

Abstract

Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor–deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

“…89,90 Alternatively, emerging studies support the notion of parenchymal macrophage repopulation in tissues and not from bone marrow, which is an interesting field of future study that may, in part, account for a lack of BrdU þ CD163 macrophages in parenchymal lesions in our study. 91,92 The Presence of CD163 þ BrdU þ Macrophages in the Meninges and Choroid Plexus Underscores Differences between CNS Compartments and a Possible Route of Viral Entry into the CNS Given that we did not observe CD163 þ BrdU þ macrophages in the perivascular space and SIVE lesions, it is interesting that we observed CD163 þ BrdU þ macrophages in the meninges and choroid plexus in numbers equal to or greater than MAC387 þ BrdU þ macrophages. This observation suggests that these two compartments are more similar to each other, and possibly to blood, than to the perivascular space and CNS parenchyma.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…They arise in the brain from early development and persist into adulthood. A long-standing controversy regarding the ontology of microglia led to a view that a subset of primitive myeloid precursors localized in the yolk sac give rise to early microglia [35][36][37]. Microglial precursors express CX3CR1 and CD45 and travel to the neuroectoderm in a matrix metalloproteinase-8-and matrix metalloproteinase-9-dependent manner [36,38].…”

“…Microglial precursors express CX3CR1 and CD45 and travel to the neuroectoderm in a matrix metalloproteinase-8-and matrix metalloproteinase-9-dependent manner [36,38]. Importantly, these are not exchanged with fetal liver or bone marrowderived hematopoietic stem cells and they possess selfrenewing capability under physiologic conditions [35,36,39,40]. The morphology and protein expression of microglia are not uniform, and this heterogeneity could explain differential microglial responses in different surroundings [41,42].…”

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

“…Microglia, the resident macrophages of the brain, are derived from early yolk sac macrophage progenitors (Ginhoux et al ., 2010; Kierdorf et al ., 2013). Under physiological conditions, there is negligible infiltration of peripheral monocytes to the brain parenchyma and the microglia population is likely sustained by self‐renewal (Ajami et al ., 2007).…”