Origin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell

Abstract

Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the late embryonic to adult brain. Its unique identity that distinguishes its “glial” features from tissue-resident macrophages resides in the fact that once entering the CNS, it is perennially exposed to a unique environment following the formation of the blood–brain barrier. Additionally, tissue-resident macrophage progenies derive from various peripheral sites that exhibit hematopoietic potential, and this has resulted in interpretation issues surrounding their origin. Intensive research endeavors have intended to track microglial progenitors during development and disease. The current review provides a corpus of recent evidence in an attempt to disentangle the birthplace of microglia from the progenitor state and underlies the molecular elements that drive microgliogenesis. Furthermore, it caters towards tracking the lineage spatiotemporally during embryonic development and outlining microglial repopulation in the mature CNS. This collection of data can potentially shed light on the therapeutic potential of microglia for CNS perturbations across various levels of severity.

Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap

“…Interestingly, studies investigating the developmental signaling pathways regulating neural crest cell migration and differentiation have identified key molecular players that are dysregulated in NCPs. This knowledge assists in developing precision medicine approaches that specifically target the underlying molecular defects in individual patients [261,262]. Emerging technologies such as induced pluripotent stem cells (iPSCs) offer a revolutionary platform for modelling NCPs in the laboratory.…”

CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease

“…To recapitulate, the emergence of BAMs is considered a complex process tightly regulated by multiple molecular cues in a similar pattern to oligodendrogenesis and microgliogenesis [24,56]. Although some molecular drivers orchestrating BAM generation have been recently discovered, it remains a largely uncharted territory.…”

“…Under homeostatic conditions, microglia are ramified [8]. Inflammatory stimuli could shift microglial morphology from ramified to amoeboid by enlarging the cell body and retracting processes [24].…”

“…During inflammation, pvMΦ extend dendritic-like processes along the perivascular space, indicating a potential chemotactic activation from surrounding cells, while meningeal macrophages prolongate their existing protrusions [63,64]. The amoeboid microglia exhibit a high phagocytic and proinflammatory phenotype [24]. As the in vivo imaging of choroid plexus remains challenging due to their deep localization in the ventricular system, the motility of cpMΦ and cp epi MΦ is yet unexplored [59].…”

“…In the past, all tissue-specific macrophages were considered to be derived from bone marrow progenitors [17][18][19]. However, according to recent data from studies that have utilized new genetic tools, the early perception that tissue-resident macrophages derive solely from adult blood circulating monocytes is no longer prevalent [8,11,[20][21][22][23][24]. Although several studies have investigated the role of microglia in neuroinflammation and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, little is known about the contribution of BAMs in these pathophysiological patterns [25][26][27][28][29][30].…”