The influence of environment and origin on brain resident macrophages and implications for therapy


Microglia are the tissue-resident macrophages of the brain and spinal cord. They are critical players in the development, normal function, and decline of the CNS. Unlike traditional monocyte-derived macrophages, microglia originate from primitive hematopoiesis in the embryonic yolk sac and self-renew throughout life. Microglia also have a unique genetic signature among tissue resident macrophages. Recent studies identify the contributions of both brain environment and developmental history to the transcriptomic identity of microglia. Here we review this emerging literature and discuss the potential implications of origin on microglial function, with particular focus on existing and future therapies using bone-marrow- or stem-cell-derived cells for the treatment of neurological diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Origin of microglia and microglia-like cells.
Fig. 2: The promise of microglia-based therapies.


  1. 1.

    Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018).

  2. 2.

    Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).

  3. 3.

    Hammond, T. R., Robinton, D. & Stevens, B. Microglia and the brain: complementary partners in development and disease. Annu. Rev. Cell Dev. Biol. 34, 523–544 (2018).

  4. 4.

    Dzierzak, E. & Bigas, A. Blood development: hematopoietic stem cell dependence and independence. Cell Stem Cell 22, 639–651 (2018).

  5. 5.

    Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999).

  6. 6.

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This study focused new attention on the origin of microglia and tissue-resident macrophages and set the stage for subsequent studies using fate-mapping to identity the nuances of macrophage origin.

  7. 7.

    Stremmel, C. et al. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat. Commun. 9, 75 (2018).

  8. 8.

    Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

  9. 9.

    Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

  10. 10.

    Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

  11. 11.

    Hoeffel, G. et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

  12. 12.

    Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).

  13. 13.

    Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

  14. 14.

    Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).

  15. 15.

    Chen, S.-K. et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775–785 (2010).

  16. 16.

    De, S. et al. Two distinct ontogenies confer heterogeneity to mouse brain microglia. Development 145, dev152306 (2018).

  17. 17.

    Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

  18. 18.

    Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929–937 (2014).

  19. 19.

    Ferrero, G. et al. Embryonic microglia derive from primitive macrophages and are replaced by cmyb-dependent definitive microglia in zebrafish. Cell Rep. 24, 130–141 (2018).

  20. 20.

    Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. V. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).

  21. 21.

    Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).

  22. 22.

    Lawson, L. J., Perry, V. H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).

  23. 23.

    Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017).

  24. 24.

    Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017).

  25. 25.

    Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

  26. 26.

    Askew, K. et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 18, 391–405 (2017).

  27. 27.

    Réu, P. et al. The lifespan and turnover of microglia in the human brain. Cell Rep. 20, 779–784 (2017).

  28. 28.

    Dai, X.-M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

  29. 29.

    Varvel, N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl Acad. Sci. USA 109, 18150–18155 (2012).

  30. 30.

    Elmore, M. R. P. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).

  31. 31.

    Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

  32. 32.

    Zhang, Y. et al. Repopulating retinal microglia restore endogenous organization and function under CX3CL1-CX3CR1. Regul. Sci. Adv. 4, p8492 (2018).

  33. 33.

    Huang, Y. et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat. Neurosci. 21, 530–540 (2018).

  34. 34.

    Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).

  35. 35.

    Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

  36. 36.

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014). This study and the following study by Lavin et al. crystallized the powerful programming effects of environment on tissue macrophages.

  37. 37.

    Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014). This study and the previous study by Gosselin et al. crystallized the powerful programming effects of environment on tissue macrophages.

  38. 38.

    Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).

  39. 39.

    Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA 113, E1738–E1746 (2016).

  40. 40.

    Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).

  41. 41.

    Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).

  42. 42.

    Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).

  43. 43.

    O’Koren, E. G. et al. Microglial function is distinct in different anatomical locations during retinal homeostasis and degeneration. Immunity 50, 723–737.e7 (2019).

  44. 44.

    Jordão, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019).

  45. 45.

    Hammond, T. R. et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50, 253–271.e6 (2019).

  46. 46.

    Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223.e10 (2019).

  47. 47.

    Van Hove, H. et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021–1035 (2019).

  48. 48.

    Wlodarczyk, A. et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36, 3292–3308 (2017).

  49. 49.

    Datta, M. et al. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Immunity 48, 514–529.e6 (2018).

  50. 50.

    Ayata, P. et al. Epigenetic regulation of brain region-specific microglia clearance activity. Nat. Neurosci. 21, 1049–1060 (2018).

  51. 51.

    Bohlen, C. J. et al. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e8 (2017).

  52. 52.

    Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018).

  53. 53.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017).

  54. 54.

    De Biase, L. M. et al. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron 95, 341–356.e6 (2017).

  55. 55.

    Shemer, A. et al. Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nat. Commun. 9, 5206 (2018). This study and the following three studies by Bennett et al., Cronk et al. and Lund et al. showed in short order that microglial transcriptomic identity is garnered by both origin and environment.

  56. 56.

    Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183.e8 (2018). This study and the three studies by Shemer et al., Cronk et al. and Lund et al. showed in short order that microglial transcriptomic identity is garnered by both origin and environment.

  57. 57.

    Cronk, J. C. et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J. Exp. Med. 215, 1627–1647 (2018). This study and the three studies by Shemer et al., Bennett et al. and Lund et al. showed in short order that microglial transcriptomic identity is garnered by both origin and environment.

  58. 58.

    Lund, H. et al. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat. Commun. 9, 4845 (2018). This study and the previous three studies by Shemer et al., Bennett et al. and Cronk et al. showed in short order that microglial transcriptomic identity is garnered by both origin and environment.

  59. 59.

    van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).

  60. 60.

    Gibson, E. M. et al. Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell 176, 43–55.e13 (2019).

  61. 61.

    Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).

  62. 62.

    Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. V. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).

  63. 63.

    Arnold, T. D. et al. Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction. J. Exp. Med. 216, 900–915 (2019).

  64. 64.

    Lund, H. et al. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nat. Immunol. 19, 1–7 (2018).

  65. 65.

    Wong, K. et al. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 18, 633–641 (2017).

  66. 66.

    Liu, Z. et al. Fate mapping via Ms4a3-expression history traces monocyte-derived cells. Cell 178, 1509–1525.e19 (2019).

  67. 67.

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).

  68. 68.

    Sagar, D. et al. Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity. Sci. Rep. 7, 2707 (2017).

  69. 69.

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

  70. 70.

    Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

  71. 71.

    Saitoh, B.-Y. et al. A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis. Mult. Scler. 19, 1367–1370 (2013).

  72. 72.

    Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).

  73. 73.

    Oosterhof, N. et al. Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am. J. Hum. Genet. 104, 936–947 (2019).

  74. 74.

    Guo, L. et al. Bi-allelic CSF1R mutations cause skeletal dysplasia of dysosteosclerosis-Pyle disease spectrum and degenerative encephalopathy with brain malformation. Am. J. Hum. Genet. 104, 925–935 (2019).

  75. 75.

    Mass, E. et al. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549, 389–393 (2017). This paper showed a stunning example of how cell of origin can influence disease expression.

  76. 76.

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

  77. 77.

    Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).

  78. 78.

    Shapiro, E. et al. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet 356, 713–718 (2000).

  79. 79.

    Peters, C. et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 104, 881–888 (2004).

  80. 80.

    Mahmood, A., Raymond, G. V., Dubey, P., Peters, C. & Moser, H. W. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 6, 687–692 (2007).

  81. 81.

    Biffi, A. et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J. Clin. Invest. 116, 3070–3082 (2006).

  82. 82.

    Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009).

  83. 83.

    Allewelt, H. et al. Long-term functional outcomes after hematopoietic stem cell transplant for early infantile Krabbe disease. Biol. Blood Marrow Transplant. 24, 2233–2238 (2018).

  84. 84.

    Boelens, J. J. et al. Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning. Blood 121, 3981–3987 (2013).

  85. 85.

    Derecki, N. C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012).

  86. 86.

    Schafer, D. P. et al. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. eLife 5, e15224 (2016).

  87. 87.

    Kwon, H.-S. et al. Anti-human CD117 antibody-mediated bone marrow niche clearance in non-human primates and humanized NSG mice. Blood 133, 2104–2108 (2019).

  88. 88.

    Capotondo, A. et al. Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc. Natl. Acad. Sci. USA 109, 15018–15023 (2012).

  89. 89.

    Muffat, J. et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358–1367 (2016).

  90. 90.

    Abud, E. M. et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293.e9 (2017).

  91. 91.

    Pandya, H. et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat. Neurosci. 20, 753–759 (2017).

  92. 92.

    Ormel, P. R. et al. Microglia innately develop within cerebral organoids. Nat. Commun. 9, 4167 (2018).

  93. 93.

    Takata, K. et al. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 47, 183–198.e6 (2017).

  94. 94.

    Sellgren, C. M. et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat. Neurosci. 22, 374–385 (2019).

  95. 95.

    Hasselmann, J. et al. Development of a chimeric model to study and manipulate human microglia in vivo. Neuron 103, 1016–1033.e10 (2019).

  96. 96.

    Pocock, J. M. & Piers, T. M. Modelling microglial function with induced pluripotent stem cells: an update. Nat. Rev. Neurosci. 19, 445–452 (2018).

  97. 97.

    Mizutani, M. et al. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J. Immunol. 188, 29–36 (2012).

  98. 98.

    Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006).

  99. 99.

    Fonseca, M. I. et al. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J. Neuroinflammation 14, 48 (2017).

  100. 100.

    Haimon, Z. et al. Re-evaluating microglia expression profiles using RiboTag and cell isolation strategies. Nat. Immunol. 19, 636–644 (2018).

  101. 101.

    Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

  102. 102.

    Samokhvalov, I. M., Samokhvalova, N. I. & Nishikawa, S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446, 1056–1061 (2007).

  103. 103.

    Luo, J. et al. Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. J. Exp. Med. 210, 157–172 (2013).

  104. 104.

    Plein, A., Fantin, A., Denti, L., Pollard, J. W. & Ruhrberg, C. Erythro-myeloid progenitors contribute endothelial cells to blood vessels. Nature 562, 223–228 (2018).

  105. 105.

    Tang, Y., Harrington, A., Yang, X., Friesel, R. E. & Liaw, L. The contribution of the Tie2+ lineage to primitive and definitive hematopoietic cells. Genesis 48, 563–567 (2010).

  106. 106.

    Maeda, K. et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat. Med. 18, 405–412 (2012).

  107. 107.

    Boyer, S. W., Schroeder, A. V., Smith-Berdan, S. & Forsberg, E. C. All hematopoietic cells develop from hematopoietic stem cells through Flk2/Flt3-positive progenitor cells. Cell Stem Cell 9, 64–73 (2011).

  108. 108.

    Witschi, R. et al. Hoxb8-Cre mice: A tool for brain-sparing conditional gene deletion. Genesis 48, 596–602 (2010).

  109. 109.

    Georgiades, P. et al. vavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages. Genesis 34, 251–256 (2002).

  110. 110.

    Orthgiess, J. et al. Neurons exhibit Lyz2 promoter activity in vivo: implications for using LysM-Cre mice in myeloid cell research. Eur. J. Immunol. 46, 1529–1532 (2016).

  111. 111.

    Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5, e13693 (2010).

  112. 112.

    Croxford, A. L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015).

  113. 113.

    Kaiser, T. & Feng, G. Tmem119-EGFP and Tmem119-CreERT2 transgenic mice for labeling and manipulating microglia. eNeuro 6, ENEURO.0448-18.2019 (2019).

  114. 114.

    Haynes, S. E. et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 9, 1512–1519 (2006).

  115. 115.

    Rojo, R. et al. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat. Commun. 10, 3215 (2019).

  116. 116.

    Villa, A. et al. Sex-specific features of microglia from adult mice. Cell Rep. 23, 3501–3511 (2018).

  117. 117.

    Pastores, G.M. & Hughes, D.A. Gaucher disease. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2000).

  118. 118.

    Aflaki, E., Westbroek, W. & Sidransky, E. The complicated relationship between Gaucher disease and Parkinsonism: insights from a rare disease. Neuron 93, 737–746 (2017).

  119. 119.

    Clarke, L.A. Mucopolysaccharidosis type I. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2002).

  120. 120.

    Scarpa, M. Mucopolysaccharidosis type II. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2007).

  121. 121.

    Orsini, J.J., Escolar, M.L., Wasserstein, M.P. & Caggana, M. Krabbe disease. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2000).

  122. 122.

    Patterson, M. Niemann-Pick disease type C. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2000).

  123. 123.

    Raymond, G.V., Moser, A.B. & Fatemi, A. X–linked adrenoleukodystrophy. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 1999).

  124. 124.

    Gomez-Ospina, N. Arylsulfatase A deficiency. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2006).

  125. 125.

    Konno, T. et al. Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur. J. Neurol. 25, 142–147 (2018).

  126. 126.

    Christodoulou, J. & Ho, G. MECP2 disorders. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2001).

  127. 127.

    Paloneva, J., Autti, T., Hakola, P. & Haltia, M.J. Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2002).

  128. 128.

    Crow, Y.J. Aicardi-Goutières syndrome. in GeneReviews (eds Adam, M. P. et al.) (University of Washington, Seattle, 2005).

  129. 129.

    Kelly, N., Makarem, D. C. & Wasserstein, M. P. Screening of newborns for disorders with high benefit-risk ratios should be mandatory. J. Law Med. Ethics 44, 231–240 (2016).

  130. 130.

    Beckmann, N. et al. Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945. Acta Neuropathol. Commun. 6, 9 (2018).

Download references


We thank the authors of the incredible works we’ve been lucky to read and attempt to honor in this manuscript; members of the Barres, Bennett, and Song-Ming labs, especially H. Song and G. Ming; members of our new clinical and research communities; and our discerning proofreaders K. Guttenplan, K. Nemec, D. Marzan, D. Barber, and A. Eisch.

Author information

M.L.B. and F.C.B. were equal contributors to the conception and writing of this review.

Correspondence to Mariko L. Bennett.

Ethics declarations

Competing interests

M.L.B and F.C.B are co-inventors on a pending patent filed by The Board of Trustees of The Leland Stanford Junior University (application 16/566,675) related to methods of microglia replacement.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bennett, M.L., Bennett, F.C. The influence of environment and origin on brain resident macrophages and implications for therapy. Nat Neurosci (2019) doi:10.1038/s41593-019-0545-6

Download citation