Skip to main content Skip to main navigation menu Skip to site footer
  • \
    Start Submission Become a Reviewer

    Microglia Heterogeneity: A Single-cell Concerto

    • Leilei Wang
    • Haoran Wu
    • Shanshan Zhang
    • Dingxian He
    • Yi Chen
    • Jingxin Xue
    • Linya You
    • Qiong Liu
    • Wensheng Li


    Abstract

    Microglia are tissue-resident macrophages of the central nervous system (CNS) that play crucial roles in development, homeostasis, and response to perturbation. Microglia react to the surrounding environment in a context-dependent manner. However, research on microglial heterogeneity is limited, given the lack of high-resolution and high-sensitivity methods. Recent studies have demonstrated the heterogeneity of microglia on a spatial-temporal scale, benefiting from the advancement of single-cell technologies. Here, we review the current knowledge about microglial diversity during physiological and pathological conditions in humans and mice.

    Keywords: microglia heterogeneity single-cell technologies disease-associated microglia
    Section

    References

    1. Agarwal, D., Sandor, C., Volpato, V., Caffrey, T. M., Monzón-Sandoval, J., Bowden, R., Webber, C. (2020). A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders. Nat Commun, 11(1), 4183. doi:10.1038/s41467-020-17876-0
    2. Askew, K., Li, K., Olmos-Alonso, A., Garcia-Moreno, F., Liang, Y., Richardson, P., Gomez-Nicola, D. (2017). Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain. Cell Rep, 18(2), 391-405. doi:10.1016/j.celrep.2016.12.041
    3. Barres, B. A., Hart, I. K., Coles, H. S., Burne, J. F., Voyvodic, J. T., Richardson, W. D., & Raff, M. C. (1992). Cell death and control of cell survival in the oligodendrocyte lineage. Cell, 70(1), 31-46. doi:10.1016/0092-8674(92)90531-g
    4. Barres, B. A., & Raff, M. C. (1999). Axonal control of oligodendrocyte development. J Cell Biol, 147(6), 1123-1128. doi:10.1083/jcb.147.6.1123
    5. Bohlen, C. J., Bennett, F. C., Tucker, A. F., Collins, H. Y., Mulinyawe, S. B., & Barres, B. A. (2017). Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures. Neuron, 94(4), 759-773.e758. doi:10.1016/j.neuron.2017.04.043
    6. Böttcher, C., Fernández-Zapata, C., Snijders, G. J. L., Schlickeiser, S., Sneeboer, M. A. M., Kunkel, D., Priller, J. (2020). Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression. Transl Psychiatry, 10(1), 310. doi:10.1038/s41398-020-00992-2
    7. Böttcher, C., Schlickeiser, S., Sneeboer, M. A. M., Kunkel, D., Knop, A., Paza, E., Priller, J. (2019). Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nat Neurosci, 22(1), 78-90. doi:10.1038/s41593-018-0290-2
    8. Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Weiner, H. L. (2014). Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci, 17(1), 131-143. doi:10.1038/nn.3599
    9. Butovsky, O., & Weiner, H. L. (2018). Microglial signatures and their role in health and disease. Nat Rev Neurosci, 19(10), 622-635. doi:10.1038/s41583-018-0057-5
    10. Colonna, M., & Butovsky, O. (2017). Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu Rev Immunol, 35, 441-468. doi:10.1146/annurev-immunol-051116-052358
    11. Darmanis, S., Sloan, S. A., Croote, D., Mignardi, M., Chernikova, S., Samghababi, P., Quake, S. R. (2017). Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma. Cell Rep, 21(5), 1399-1410. doi:10.1016/j.celrep.2017.10.030
    12. De Biase, L. M., Schuebel, K. E., Fusfeld, Z. H., Jair, K., Hawes, I. A., Cimbro, R., Bonci, A. (2017). Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia. Neuron, 95(2), 341-356.e346. doi:10.1016/j.neuron.2017.06.020
    13. Flowers, A., Bell-Temin, H., Jalloh, A., Stevens, S. M., Jr., & Bickford, P. C. (2017). Proteomic anaysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response. J Neuroinflammation, 14(1), 96. doi:10.1186/s12974-017-0840-7
    14. Friebel, E., Kapolou, K., Unger, S., Núñez, N. G., Utz, S., Rushing, E. J., Becher, B. (2020). Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes. Cell, 181(7), 1626-1642.e1620. doi:10.1016/j.cell.2020.04.055
    15. Gerrits, E., Heng, Y., Boddeke, E., & Eggen, B. J. L. (2020). Transcriptional profiling of microglia; current state of the art and future perspectives. Glia, 68(4), 740-755. doi:10.1002/glia.23767
    16. Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., Rodewald, H. R. (2015). Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature, 518(7540), 547-551. doi:10.1038/nature13989
    17. Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Glass, C. K. (2017). An environment-dependent transcriptional network specifies human microglia identity. Science, 356(6344). doi:10.1126/science.aal3222
    18. Grabert, K., Michoel, T., Karavolos, M. H., Clohisey, S., Baillie, J. K., Stevens, M. P., McColl, B. W. (2016). Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci, 19(3), 504-516. doi:10.1038/nn.4222
    19. Guneykaya, D., Ivanov, A., Hernandez, D. P., Haage, V., Wojtas, B., Meyer, N., Wolf, S. A. (2018). Transcriptional and Translational Differences of Microglia from Male and Female Brains. Cell Rep, 24(10), 2773-2783.e2776. doi:10.1016/j.celrep.2018.08.001
    20. Hambardzumyan, D., Gutmann, D. H., & Kettenmann, H. (2016). The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci, 19(1), 20-27. doi:10.1038/nn.4185
    21. Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Stevens, B. (2019). Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity, 50(1), 253-271.e256. doi:10.1016/j.immuni.2018.11.004
    22. Hanamsagar, R., Alter, M. D., Block, C. S., Sullivan, H., Bolton, J. L., & Bilbo, S. D. (2017). Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia, 65(9), 1504-1520. doi:10.1002/glia.23176
    23. Hickman, S. E., & El Khoury, J. (2014). TREM2 and the neuroimmunology of Alzheimer's disease. Biochem Pharmacol, 88(4), 495-498. doi:10.1016/j.bcp.2013.11.021
    24. Hughes, A. N., & Appel, B. (2020). Microglia phagocytose myelin sheaths to modify developmental myelination. Nat Neurosci, 23(9), 1055-1066. doi:10.1038/s41593-020-0654-2
    25. Jeong, H. K., Jou, I., & Joe, E. H. (2010). Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra. Exp Mol Med, 42(12), 823-832. doi:10.3858/emm.2010.42.12.085
    26. Jia, X., Gao, Z., & Hu, H. (2021). Microglia in depression: current perspectives. Sci China Life Sci, 64(6), 911-925. doi:10.1007/s11427-020-1815-6
    27. Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Stefansson, K. (2013). Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med, 368(2), 107-116. doi:10.1056/NEJMoa1211103
    28. Jordão, M. J. C., Sankowski, R., Brendecke, S. M., Sagar, Locatelli, G., Tai, Y. H., Prinz, M. (2019). Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science, 363(6425). doi:10.1126/science.aat7554
    29. Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., Amit, I. (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell, 169(7), 1276-1290.e1217. doi:10.1016/j.cell.2017.05.018
    30. Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., Prinz, M. (2013). Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci, 16(3), 273-280. doi:10.1038/nn.3318
    31. Kierdorf, K., & Prinz, M. (2017). Microglia in steady state. J Clin Invest, 127(9), 3201-3209. doi:10.1172/jci90602
    32. Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Butovsky, O. (2017). The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity, 47(3), 566-581.e569. doi:10.1016/j.immuni.2017.08.008
    33. Ladeby, R., Wirenfeldt, M., Garcia-Ovejero, D., Fenger, C., Dissing-Olesen, L., Dalmau, I., & Finsen, B. (2005). Microglial cell population dynamics in the injured adult central nervous system. Brain Res Brain Res Rev, 48(2), 196-206. doi:10.1016/j.brainresrev.2004.12.009
    34. Lawson, L. J., Perry, V. H., Dri, P., & Gordon, S. (1990). Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience, 39(1), 151-170. doi:10.1016/0306-4522(90)90229-w
    35. Li, Q., Cheng, Z., Zhou, L., Darmanis, S., Neff, N. F., Okamoto, J., Barres, B. A. (2019). Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron, 101(2), 207-223.e210. doi:10.1016/j.neuron.2018.12.006
    36. Liu, W., Venugopal, S., Majid, S., Ahn, I. S., Diamante, G., Hong, J., Chandler, S. H. (2020). Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis. Neurobiol Dis, 141, 104877. doi:10.1016/j.nbd.2020.104877
    37. Lopes, K. d. P., Snijders, G. J. L., Humphrey, J., Allan, A., Sneeboer, M. A. M., Navarro, E., Raj, T. (2022). Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies. Nature Genetics, 54(1), 4-17. doi:10.1038/s41588-021-00976-y
    38. Mastroeni, D., Nolz, J., Sekar, S., Delvaux, E., Serrano, G., Cuyugan, L., Coleman, P. D. (2018). Laser-captured microglia in the Alzheimer's and Parkinson's brain reveal unique regional expression profiles and suggest a potential role for hepatitis B in the Alzheimer's brain. Neurobiol Aging, 63, 12-21. doi:10.1016/j.neurobiolaging.2017.10.019
    39. Masuda, T., Sankowski, R., Staszewski, O., Böttcher, C., Amann, L., Sagar, Prinz, M. (2019). Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature, 566(7744), 388-392. doi:10.1038/s41586-019-0924-x
    40. Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Amit, I. (2016). Microglia development follows a stepwise program to regulate brain homeostasis. Science, 353(6301), aad8670. doi:10.1126/science.aad8670
    41. Ochocka, N., Segit, P., Walentynowicz, K. A., Wojnicki, K., Cyranowski, S., Swatler, J., Kaminska, B. (2021). Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages. Nat Commun, 12(1), 1151. doi:10.1038/s41467-021-21407-w
    42. Olah, M., Menon, V., Habib, N., Taga, M. F., Ma, Y., Yung, C. J., De Jager, P. L. (2020). Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease. Nat Commun, 11(1), 6129. doi:10.1038/s41467-020-19737-2
    43. Piancone, F., La Rosa, F., Marventano, I., Saresella, M., & Clerici, M. (2021). The Role of the Inflammasome in Neurodegenerative Diseases. Molecules, 26(4). doi:10.3390/molecules26040953
    44. Plemel, J. R., Stratton, J. A., Michaels, N. J., Rawji, K. S., Zhang, E., Sinha, S., Yong, V. W. (2020). Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion. Sci Adv, 6(3), eaay6324. doi:10.1126/sciadv.aay6324
    45. Ransohoff, R. M., & Perry, V. H. (2009). Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol, 27, 119-145. doi:10.1146/annurev.immunol.021908.132528
    46. Réu, P., Khosravi, A., Bernard, S., Mold, J. E., Salehpour, M., Alkass, K., Frisén, J. (2017). The Lifespan and Turnover of Microglia in the Human Brain. Cell Rep, 20(4), 779-784. doi:10.1016/j.celrep.2017.07.004
    47. Sankowski, R., Böttcher, C., Masuda, T., Geirsdottir, L., Sagar, Sindram, E., Prinz, M. (2019). Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat Neurosci, 22(12), 2098-2110. doi:10.1038/s41593-019-0532-y
    48. Schmid, C. D., Sautkulis, L. N., Danielson, P. E., Cooper, J., Hasel, K. W., Hilbush, B. S., Carson, M. J. (2002). Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem, 83(6), 1309-1320. doi:10.1046/j.1471-4159.2002.01243.x
    49. Schulz, C., Gomez Perdiguero, E., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Geissmann, F. (2012). A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science, 336(6077), 86-90. doi:10.1126/science.1219179
    50. Schwarz, J. M., Sholar, P. W., & Bilbo, S. D. (2012). Sex differences in microglial colonization of the developing rat brain. J Neurochem, 120(6), 948-963. doi:10.1111/j.1471-4159.2011.07630.x
    51. See, P., Dutertre, C. A., Chen, J., Günther, P., McGovern, N., Irac, S. E., . . . Ginhoux, F. (2017). Mapping the human DC lineage through the integration of high-dimensional techniques. Science, 356(6342). doi:10.1126/science.aag3009
    52. Sheng, J. G., Mrak, R. E., & Griffin, W. S. (1998). Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol, 95(3), 229-234. doi:10.1007/s004010050792
    53. Smajić, S., Prada-Medina, C. A., Landoulsi, Z., Ghelfi, J., Delcambre, S., Dietrich, C., Spielmann, M. (2021). Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain. doi:10.1093/brain/awab446
    54. Smith, A. M., Davey, K., Tsartsalis, S., Khozoie, C., Fancy, N., Tang, S. S., Matthews, P. M. (2022). Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology. Acta Neuropathol, 143(1), 75-91. doi:10.1007/s00401-021-02372-6
    55. Soreq, L., Rose, J., Soreq, E., Hardy, J., Trabzuni, D., Cookson, M. R., Ule, J. (2017). Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging. Cell Rep, 18(2), 557-570. doi:10.1016/j.celrep.2016.12.011
    56. Sousa, C., Golebiewska, A., Poovathingal, S. K., Kaoma, T., Pires-Afonso, Y., Martina, S., Michelucci, A. (2018). Single-cell transcriptomics reveals distinct inflammation-induced microglia signatures. EMBO Rep, 19(11). doi:10.15252/embr.201846171
    57. Stoeckius, M., Hafemeister, C., Stephenson, W., Houck-Loomis, B., Chattopadhyay, P. K., Swerdlow, H., Smibert, P. (2017). Simultaneous epitope and transcriptome measurement in single cells. Nat Methods, 14(9), 865-868. doi:10.1038/nmeth.4380
    58. Venteicher, A. S., Tirosh, I., Hebert, C., Yizhak, K., Neftel, C., Filbin, M. G., Suvà, M. L. (2017). Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science, 355(6332). doi:10.1126/science.aai8478
    59. Villa, A., Gelosa, P., Castiglioni, L., Cimino, M., Rizzi, N., Pepe, G., Maggi, A. (2018). Sex-Specific Features of Microglia from Adult Mice. Cell Rep, 23(12), 3501-3511. doi:10.1016/j.celrep.2018.05.048
    60. Wang, Y. L., Han, Q. Q., Gong, W. Q., Pan, D. H., Wang, L. Z., Hu, W., Liu, Q. (2018). Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats. J Neuroinflammation, 15(1), 21. doi:10.1186/s12974-018-1054-3
    61. Wang, Y. L., Wu, H. R., Zhang, S. S., Xiao, H. L., Yu, J., Ma, Y. Y., Liu, Q. (2021). Catalpol ameliorates depressive-like behaviors in CUMS mice via oxidative stress-mediated NLRP3 inflammasome and neuroinflammation. Transl Psychiatry, 11(1), 353. doi:10.1038/s41398-021-01468-7
    62. Young, A. M. H., Kumasaka, N., Calvert, F., Hammond, T. R., Knights, A., Panousis, N., Gaffney, D. J. (2021). A map of transcriptional heterogeneity and regulatory variation in human microglia. Nat Genet, 53(6), 861-868. doi:10.1038/s41588-021-00875-2
    63. Zhao, J., Bi, W., Xiao, S., Lan, X., Cheng, X., Zhang, J., Zhu, L. (2019). Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Scientific reports, 9(1), 5790. doi:10.1038/s41598-019-42286-8
    64. Zhong, J., Tang, G., Zhu, J., Wu, W., Li, G., Lin, X., Chen, D. (2021). Single-cell brain atlas of Parkinson's disease mouse model. J Genet Genomics, 48(4), 277-288. doi:10.1016/j.jgg.2021.01.003
    65. Zhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Colonna, M. (2020). Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nat Med, 26(1), 131-142. doi:10.1038/s41591-019-0695-9

    How to Cite

    Wang, Leilei, et al. “Microglia Heterogeneity: A Single-Cell Concerto”. Human Brain, vol. 1, no. 1, July 2022, pp. 77–91, doi:10.37819/hb.001.001.0208.
    ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
    Download Citation
    Endnote/Zotero/Mendeley (RIS) BibTeX

    HTML
    313

    Total
    233 25

    Share

    Search Panel

    Leilei Wang
    Google Scholar
    Pubmed
    JDMFS Journal

    Haoran Wu
    Google Scholar
    Pubmed
    JDMFS Journal

    Shanshan Zhang
    Google Scholar
    Pubmed
    JDMFS Journal

    Dingxian He
    Google Scholar
    Pubmed
    JDMFS Journal

    Yi Chen
    Google Scholar
    Pubmed
    JDMFS Journal

    Jingxin Xue
    Google Scholar
    Pubmed
    JDMFS Journal

    Linya You
    Google Scholar
    Pubmed
    JDMFS Journal

    Qiong Liu
    Google Scholar
    Pubmed
    JDMFS Journal

    Wensheng Li
    Google Scholar
    Pubmed
    JDMFS Journal

    Downloads

    Article Details

    DOI: https://doi.org/10.37819/hb.001.001.0208

    Published: 2022-07-12

    Most Read This Month

    License

    Copyright (c) 2022 Leilei Wang, Haoran Wu, Shanshan Zhang, Dingxian He, Yi Chen , Jingxin Xue, Linya You, Qiong Liu, Wensheng Li

    Creative Commons License

    This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.

    Most read articles by the same author(s)

    Copyright © 2023 EurAsia Academic Publishing Group. All rights reserved