Cited by 401Neuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanismsBarrier Structure and Function Studies

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The origin and cell lineage of microglia: new concepts

Chan, W.Y., Kohsaka, S., Rezaie, P.·2007·Brain Research Reviews

DOI 10.1016/j.brainresrev.2006.11.002

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Abstract

Despite intense study, the precise origin and cell lineage of microglia, the resident mononuclear phagocytes of the nervous system, are still a matter for debate. Unlike macroglia (astrocytes and oligodendrocytes) and neurons, which are derived from neuroectoderm, microglial progenitors arise from peripheral mesodermal (myeloid) tissue. The view still commonly held is that tissue-resident mononuclear phagocytes (including microglia) are derived from circulating blood monocytes and these take up residence late in gestation and postnatally. However, microglial progenitors colonise the nervous system primarily during embryonic and fetal periods of development. Recent evidence indicates differences between the lineage of mononuclear phagocytes during the embryonic and fetal period from that in the neonate and adult-mononuclear phagocytes that take up residence within tissues are derived from a lineage of myeloid cells that is independent of the monocyte lineage. Our own findings on the development and differentiation of microglial progenitors, taken together with findings by other investigators, and in the context of the heterogeneity between myeloid differentiation in the fetus and in the adult, support the view that microglia are derived prenatally from mesodermal progenitors that are distinct from monocytes. Furthermore, microglial progenitors colonise the nervous system via extravascular routes initially. These findings challenge the concept that resident microglia in the nervous system are derived from circulating blood monocytes. Work is still underway to establish the tissue of origin and lineage of microglial progenitors in vivo. This information is critical not only from a developmental perspective, but significantly from a therapeutic viewpoint, as (i) the unique property of microglial progenitors to colonise the nervous system from the periphery allows these cells to be exploited as a biological and non-invasive means for cell therapy by delivering genes to the nervous system (microglial engraftment), and (ii) there are indications that microglial progenitors are specifically able to home to the nervous system. Use of microglial progenitors for therapeutic purposes becomes feasible only if the origin and cell lineage of these microglial progenitors are known and these cells can be isolated and manipulated in vitro (i.e., to express specific trophic factors) prior to therapeutic transfer (e.g., intravenously) in vivo. In this paper, we shall briefly consider the existing concepts on the origin and lineage of microglial progenitors and discuss new hypotheses in the light of emerging data that suggest clear differences between fetal and adult ontogeny of myeloid cells.

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“Unlike astrocytes and oligodendrocytes (so-called macroglia), which are of neuroectodermal origin, microglia are of mesodermal origin, arising from progenitor cells that migrate prenatally to the central nervous system (Chan, Kohsaka, and Rezaie 2007).”
Background
Microglia-specific NF-κB signaling is a critical regulator of prion-induced glial inflammation and neuronal loss
Hay, A. J. D., Popichak, K. A., Mumford, G., Shirley, P. M., Bian, J., Wolfrath, L., Lei, S., Eggers, M., Nicholson, E. M., Tjalkens, R. B., et al. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1012582 · Cited by 12
The use of glial data in human health assessments of environmental contaminants
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“For example, as some researchers contend that, similar to macrophages, microglia are derived from hematopoietic precursors and populate the CNS during development (Chan et al., 2007), exposure”
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Mechanisms of cellular plasticity in cerebral perivascular region
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Tyro3 receptor tyrosine kinases in the heterogeneity of apoptotic cell uptake
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“Resident tissue macrophages derive ultimately from hematopoietic precursors, but there is evidence that in the absence of inflammation in some organs, their numbers are sustained primarily by local proliferation (89-92).”
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Roles of Toll-Like Receptors in Pathophysiology of Alzheimer’s Disease and Multiple Sclerosis
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Beneficial effects of chlorogenic acid treatment on neuroinflammation after deep hypothermic circulatory arrest may be mediated through CYLD/NF-κB signaling
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Retracted: Superoxide‐dependent uptake of vitamin C in human glioma cells
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Retracted
Function and Phenotype of Microglia Are Determined by Toll-Like Receptor 2/Toll-Like Receptor 4 Activation Sequence
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“Glia cells are comprised of oligodendrocytes, astrocytes, and microglia (Chan et al. , 2007).”
Pertussis Toxin Ameliorates Microglial Activation Associated With Ischemic Stroke
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“Microglia are perhaps the most important intrinsic cerebral immune cells, constituting approximately 5% to 10% of total number of brain cells (Chan et al., 2007; Li and Barres, 2018).”
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Calcium Signaling in Glioma Cells: The Role of Nucleotide Receptors
Wypych, D., & Pomorski, P. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-30651-9_4 · Cited by 9
Modeling neuro-immune interactions using human pluripotent stem cells
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Historical Context
Rezaie, P., & Hanisch, U. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1429-6_2 · Cited by 7
Cannabinoid Signaling Through Non-CB1R/Non-CB2R Targets in Microglia
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Blocking mPTP on Neural Stem Cells and Activating the Nicotinic Acetylcholine Receptor α7 Subunit on Microglia Attenuate Aβ-Induced Neurotoxicity on Neural Stem Cells
Chen, Q., Wang, K., Jiang, D., Wang, Y., Xiao, X., Zhu, N., Li, M., Jia, S., & Wang, Y. (2016) · Neurochemical Research · doi:10.1007/s11064-016-1862-8 · Cited by 7
“Microglia are highly specific resident immune cells that act as the first and main form of active immune defense in the central nervous system [6].”
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Glial Cells as Key Mediators in the Pathophysiology of Neurodegenerative Diseases
Bogus, K., Marchesi, N., Campagnoli, L. I. M., Pascale, A., & Pałasz, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020884 · Cited by 10
“Beyond their conventional neuromodulatory function, they also contribute to neuroendocrine regulation as well as neurogenesis [55,56].”
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Mechanisms of Seizure during Pregnancy and Preeclampsia
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Interactions between glia, the immune system and pain processes during early development
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Perspectives of Stem Cells
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Human Adipose-Stem-Cell-Derived Small Extracellular Vesicles Modulate Behavior and Glial Cells in Young and Aged Mice Following TBI
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“In young brains, microglia maintain a balanced response to injury, aiding neuroprotection [16,17].”
Development of a novel purification protocol to isolate and identify brain microglia
Doughty, D., Rajpurohit, S. K., Trang, A., Alptekin, A., Korkaya, A. K., Achyut, B. R., Arbab, A. S., & Bradford, J. W. (2022) · Experimental Biology and Medicine · doi:10.1177/15353702221096060 · Cited by 6
“Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion.”
Background
Aging and neurodegeneration: when systemic dysregulations affect brain macrophage heterogeneity
Joly, P., Labsy, R., & Silvin, A. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkae034 · Cited by 5
Critical Role of Neuronal Vps35 in Blood Vessel Branching and Maturation in Developing Mouse Brain
Zhao, Y., Lee, D., Zhu, X., & Xiong, W. (2022) · Biomedicines · doi:10.3390/biomedicines10071653 · Cited by 4
Anti-inflammatory microglial cell function in the light of the latest scientific research
Łabuzek, K., Skrudlik, E., Gabryel, B., & Okopień, B. (2015) · Annales Academiae Medicae Silesiensis · doi:10.18794/aams/32608 · Cited by 4
Neural Progenitor Cell- and Developing Neuron-Derived Extracellular Vesicles Differentially Modulate Microglial Activation
Chiu, T., Huang, H., Liew, H., Chang, H., Wu, H.-R., & Wang, M.-J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157099 · Cited by 3
Time-Delay Estimation Of The Line-Of-Sight Signal In A Multipath Environment
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Effect of Microglial Inflammation in Prion Disease
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“Meanwhile, microglial cytotoxic functions are increased due to cytokine stimulation by other immune cells with the release of NO• (Banati et al., 1993), such as superoxide (Chan et al., 2007).”
Origin and Development of Microglia
Patro, N., & Patro, I. K. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_7 · Cited by 3
History of Microglia
Rezaie, P., & Hanisch, U. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_2 · Cited by 3
Perspectives of Stem Cell-Derived Microglia for Medicine
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“The exact origin of microglia is still unclear, but several reports suggest that microglia are of myeloid origin (Chan et al., 2007).”
Response to Watkins and Hutchinson
Smith, A. M., & Dragunow, M. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.02.005 · Cited by 3
The Origin of Microglia and the Development of the Brain
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“These cells are derived from circulating progenitors (probably monocytes), and give rise to socalled ameboid microglia (Rezaie and Male, 2002; Simard and Rivest, 2004; Rezaie et al., 2005; Tsuchiya et al., 2005; Chan et al., 2007).”
BackgroundInfluential
SK-Channel Activation Alters Peripheral Metabolic Pathways in Mice, but Not Lipopolysaccharide-Induced Fever or Inflammation
Bredehöft, J., Dolga, A. M., Honrath, B., Wache, S., Mazurek, S., Culmsee, C., Schoemaker, R. G., Gerstberger, R., Roth, J., & Rummel, C. (2022) · Journal of Inflammation Research · doi:10.2147/jir.s338812 · Cited by 3
“Microglia are the most important immune-system cells in the brain.(10,11) Their involvement in neuroinflammatory processes has been well described and broadly discussed, eg, using models of microglia depletion in organotypic brain slice cultures or in vivo.”
Background
SK-Channel Activation Alters Peripheral Metabolic Pathways in Mice, but Not Lipopolysaccharide-Induced Fever or Inflammation
Bredehöft, J., Dolga, A. M., Honrath, B., Wache, S., Mazurek, S., Culmsee, C., Schoemaker, R. G., Gerstberger, R., Roth, J., & Rummel, C. D. (2022) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 3
Update on the interaction of notch and Wnt/β-catenin signaling in neural stem cells and brain homeostasis during ischemic stroke
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Development of early biomarkers of Alzheimer's disease: A precision medicine perspective
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Microglial physiology and function
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Lessons from In Vivo Imaging
Davalos, D., & Fuhrmann, M. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1429-6_4 · Cited by 2

Authors: Chan, W. Y., Kohsaka, S., & Rezaie, P.
Affiliations: Chinese University of Hong Kong (HK)
National Institute of Neuroscience (JP)
King's College London (GB)
ORCID: Chan, W.Y.
Kohsaka, S.
Venue: Brain Research Reviews
Publisher: Elsevier BV
Published: 2007-02
Volume: 53
Issue: 2
Pages: 344-354
ISSN: 0165-0173 (ISSN-L)
DOI: 10.1016/j.brainresrev.2006.11.002
OpenAlex: W2087954391
Cited by: 400
References: 53
Citations by year: 2026: 6 · 2025: 9 · 2024: 8 · 2023: 13 · 2022: 15 · 2021: 19 · 2020: 17 · 2019: 10 · 2018: 13 · 2017: 19 · 2016: 23 · 2015: 28 · 2014: 32 · 2013: 41 · 2012: 38
FWCI: 2.19
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Brain Research Reviews (publishedVersion)
PubMed (publishedVersion)
Open Research Online - ORO (The Open University) (submittedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: microglia, cell lineage, embryonic and fetal development, cell therapy, trophic factors, brain development, trophoblast
MeSH terms: Animals, Cell Differentiation, Humans, Models, Biological, Stem Cells, Microglia, Cell Lineage

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The origin and cell lineage of microglia: new concepts

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