Abstract
Glial cells, including astrocytes, oligodendrocytes, and microglia, are the major components in the central nervous system (CNS). Studies have revealed the heterogeneity of each glial cell type and that they each may play distinct roles in physiological processes and/or neurological diseases. Single-cell sequencing (scRNA-seq) technology developed in recent years has extended our understanding of glial cell heterogeneity from the perspective of transcriptome profiling. This review summarizes the marker genes of major glial cells in the CNS and reveals their heterogeneity in different species, CNS regions, developmental stages, and pathological states (Alzheimer’s disease and spinal cord injury), expanding our knowledge of glial cell heterogeneity on both molecular and functional levels.
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Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25. https://doi.org/10.1016/j.nbd.2009.07.030
Akay LA, Effenberger AH, Tsai LH (2021) Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function. Genes Dev 35(3–4):180–198. https://doi.org/10.1101/gad.344218.120
Allen NJ, Lyons DA (2018) Glia as architects of central nervous system formation and function. Science 362(6411):181–185. https://doi.org/10.1126/science.aat0473
Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, Barres BA (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486(7403):410–414. https://doi.org/10.1038/nature11059
Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R et al (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532(7598):195–200. https://doi.org/10.1038/nature17623
Armingol E, Officer A, Harismendy O, Lewis NE (2021) Deciphering cell-cell interactions and communication from gene expression. Nat Rev Genet 22(2):71–88. https://doi.org/10.1038/s41576-020-00292-x
Assinck P, Duncan GJ, Plemel JR, Lee MJ, Stratton JA, Manesh SB et al (2017) Myelinogenic plasticity of oligodendrocyte precursor cells following spinal cord contusion injury. J Neurosci 37(36):8635–8654. https://doi.org/10.1523/JNEUROSCI.2409-16.2017
Avraham O, Deng PY, Jones S, Kuruvilla R, Semenkovich CF, Klyachko VA, Cavalli V (2020) Satellite glial cells promote regenerative growth in sensory neurons. Nat Commun 11(1):4891. https://doi.org/10.1038/s41467-020-18642-y
Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE et al (2018) Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci 21(8):1049–1060. https://doi.org/10.1038/s41593-018-0192-3
Barnabe-Heider F, Goritz C, Sabelstrom H, Takebayashi H, Pfrieger FW, Meletis K, Frisen J (2010) Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell 7(4):470–482. https://doi.org/10.1016/j.stem.2010.07.014
Bartus K, Burnside ER, Galino J, James ND, Bennett DLH, Bradbury EJ (2019) ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury. Glia 67(6):1036–1046. https://doi.org/10.1002/glia.23586
Batiuk MY, de Vin F, Duque SI, Li C, Saito T, Saido T et al (2017) An immunoaffinity-based method for isolating ultrapure adult astrocytes based on ATP1B2 targeting by the ACSA-2 antibody. J Biol Chem 292(21):8874–8891. https://doi.org/10.1074/jbc.M116.765313
Batiuk MY, Martirosyan A, Wahis J, de Vin F, Marneffe C, Kusserow C et al (2020) Identification of region-specific astrocyte subtypes at single cell resolution. Nat Commun 11(1):1220. https://doi.org/10.1038/s41467-019-14198-8
Bayraktar OA, Fuentealba LC, Alvarez-Buylla A, Rowitch DH (2014) Astrocyte development and heterogeneity. Cold Spring Harb Perspect Biol 7(1):a020362. https://doi.org/10.1101/cshperspect.a020362
Bayraktar OA, Bartels T, Holmqvist S, Kleshchevnikov V, Martirosyan A, Polioudakis D et al (2020) Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat Neurosci 23(4):500–509. https://doi.org/10.1038/s41593-020-0602-1
Bellver-Landete V, Bretheau F, Mailhot B, Vallieres N, Lessard M, Janelle ME et al (2019) Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun 10(1):518. https://doi.org/10.1038/s41467-019-08446-0
Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB et al (2016) New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA 113(12):E1738-1746. https://doi.org/10.1073/pnas.1525528113
Bennett FC, Bennett ML, Yaqoob F, Mulinyawe SB, Grant GA, Hayden Gephart M et al (2018) A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98(6):1170-1183.e1178. https://doi.org/10.1016/j.neuron.2018.05.014
Bercury KK, Macklin WB (2015) Dynamics and mechanisms of CNS myelination. Dev Cell 32(4):447–458. https://doi.org/10.1016/j.devcel.2015.01.016
Blum JA, Klemm S, Shadrach JL, Guttenplan KA, Nakayama L, Kathiria A et al (2021) Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons. Nat Neurosci 24(4):572–583. https://doi.org/10.1038/s41593-020-00795-0
Bohlen CJ, Bennett FC, Bennett ML (2019a) Isolation and culture of microglia. Curr Protoc Immunol 125(1):e70. https://doi.org/10.1002/cpim.70
Bohlen CJ, Friedman BA, Dejanovic B, Sheng M (2019b) Microglia in brain development, homeostasis, and neurodegeneration. Annu Rev Genet 53:263–288. https://doi.org/10.1146/annurev-genet-112618-043515
Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ (2018) The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22(1):269–285. https://doi.org/10.1016/j.celrep.2017.12.039
Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML, Snyder MP et al (2015) Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523(7561):486–490. https://doi.org/10.1038/nature14590
Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278. https://doi.org/10.1523/JNEUROSCI.4178-07.2008
Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER (2019) Astrocyte biomarkers in Alzheimer’s disease. Trends Mol Med 25(2):77–95. https://doi.org/10.1016/j.molmed.2018.11.006
Chaboub LS, Manalo JM, Lee HK, Glasgow SM, Chen F, Kawasaki Y et al (2016) Temporal profiling of astrocyte precursors reveals parallel roles for asef during development and after injury. J Neurosci 36(47):11904–11917. https://doi.org/10.1523/JNEUROSCI.1658-16.2016
Chai H, Diaz-Castro B, Shigetomi E, Monte E, Octeau JC, Yu X et al (2017) Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95(3):531-549.e539. https://doi.org/10.1016/j.neuron.2017.06.029
Chen J, Poskanzer KE, Freeman MR, Monk KR (2020) Live-imaging of astrocyte morphogenesis and function in zebrafish neural circuits. Nat Neurosci 23(10):1297–1306. https://doi.org/10.1038/s41593-020-0703-x
Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433. https://doi.org/10.1016/j.cell.2004.12.020
Clark IC, Gutierrez-Vazquez C, Wheeler MA, Li Z, Rothhammer V, Linnerbauer M et al (2021) Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science. https://doi.org/10.1126/science.abf1230
Crawford AH, Tripathi RB, Richardson WD, Franklin RJM (2016) Developmental origin of oligodendrocyte lineage cells determines response to demyelination and susceptibility to age-associated functional decline. Cell Rep 15(4):761–773. https://doi.org/10.1016/j.celrep.2016.03.069
Cusanovich DA, Hill AJ, Aghamirzaie D, Daza RM, Pliner HA, Berletch JB et al (2018) A single-cell atlas of in vivo mammalian chromatin accessibility. Cell 174(5):1309-1324.e1318. https://doi.org/10.1016/j.cell.2018.06.052
Dang TC, Ishii Y, Nguyen V, Yamamoto S, Hamashima T, Okuno N et al (2019) Powerful homeostatic control of oligodendroglial lineage by PDGFRalpha in adult brain. Cell Rep 27(4):1073-1089.e1075. https://doi.org/10.1016/j.celrep.2019.03.084
Del-Aguila JL, Li Z, Dube U, Mihindukulasuriya KA, Budde JP, Fernandez MV et al (2019) A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain. Alzheimers Res Ther 11(1):71. https://doi.org/10.1186/s13195-019-0524-x
Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52(6):953–968. https://doi.org/10.1016/j.neuron.2006.11.019
Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Plemel JR, Tetzlaff W (2020) The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury. Glia 68(2):227–245. https://doi.org/10.1002/glia.23706
Elbaz B, Popko B (2019) Molecular control of oligodendrocyte development. Trends Neurosci 42(4):263–277. https://doi.org/10.1016/j.tins.2019.01.002
Emery B, Dugas JC (2013) Purification of oligodendrocyte lineage cells from mouse cortices by immunopanning. Cold Spring Harb Protoc 2013(9):854–868. https://doi.org/10.1101/pdb.prot073973
Escartin C, Galea E, Lakatos A, O’Callaghan JP, Petzold GC, Serrano-Pozo A et al (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 24(3):312–325. https://doi.org/10.1038/s41593-020-00783-4
Floriddia EM, Lourenco T, Zhang S, van Bruggen D, Hilscher MM, Kukanja P et al (2020) Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury. Nat Commun 11(1):5860. https://doi.org/10.1038/s41467-020-19453-x
Fogarty M, Richardson WD, Kessaris N (2005) A subset of oligodendrocytes generated from radial glia in the dorsal spinal cord. Development 132(8):1951–1959. https://doi.org/10.1242/dev.01777
Foo LC (2013) Purification of rat and mouse astrocytes by immunopanning. Cold Spring Harb Protoc 2013(5):421–432. https://doi.org/10.1101/pdb.prot074211
Fu H, Zhao Y, Hu D, Wang S, Yu T, Zhang L (2020) Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice. Cell Death Dis 11(7):528. https://doi.org/10.1038/s41419-020-2733-4
Fujikawa A, Noda M (2016) Role of pleiotrophin-protein tyrosine phosphatase receptor type Z signaling in myelination. Neural Regen Res 11(4):549–551. https://doi.org/10.4103/1673-5374.180761
Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR et al (2017) Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci 20(8):1162–1171. https://doi.org/10.1038/nn.4597
Garcia JA, Cardona SM, Cardona AE (2014) Isolation and analysis of mouse microglial cells. Curr Protoc Immunol 104:143511–143515. https://doi.org/10.1002/0471142735.im1435s104
Ge WP, Miyawaki A, Gage FH, Jan YN, Jan LY (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484(7394):376–380. https://doi.org/10.1038/nature10959
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. https://doi.org/10.1126/science.1194637
Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518(7540):547–551. https://doi.org/10.1038/nature13989
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP et al (2016) Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci 19(3):504–516. https://doi.org/10.1038/nn.4222
Grassivaro F, Menon R, Acquaviva M, Ottoboni L, Ruffini F, Bergamaschi A et al (2020) Convergence between microglia and peripheral macrophages phenotype during development and neuroinflammation. J Neurosci 40(4):784–795. https://doi.org/10.1523/JNEUROSCI.1523-19.2019
Greenhalgh AD, David S, Bennett FC (2020) Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 21(3):139–152. https://doi.org/10.1038/s41583-020-0263-9
Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C et al (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22(12):2087–2097. https://doi.org/10.1038/s41593-019-0539-4
Guttenplan KA, Liddelow SA (2019) Astrocytes and microglia: mod{guttenplan, 2019 #9}els and tools. J Exp Med 216(1):71–83. https://doi.org/10.1084/jem.20180200
Hackett AR, Yahn SL, Lyapichev K, Dajnoki A, Lee DH, Rodriguez M et al (2018) Injury type-dependent differentiation of NG2 glia into heterogeneous astrocytes. Exp Neurol 308:72–79. https://doi.org/10.1016/j.expneurol.2018.07.001
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A et al (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. https://doi.org/10.1016/j.immuni.2018.11.004
Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S et al (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12(3):342–353. https://doi.org/10.1016/j.stem.2012.12.015
Hastings MH, Maywood ES, Brancaccio M (2018) Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci 19(8):453–469. https://doi.org/10.1038/s41583-018-0026-z
He Z, Jin Y (2016) Intrinsic control of axon regeneration. Neuron 90(3):437–451. https://doi.org/10.1016/j.neuron.2016.04.022
Herrero-Navarro A, Puche-Aroca L, Moreno-Juan V, Sempere-Ferrandez A, Espinosa A, Susin R et al (2021) Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming. Sci Adv. https://doi.org/10.1126/sciadv.abe8978
Hodge RD, Bakken TE, Miller JA, Smith KA, Barkan ER, Graybuck LT et al (2019) Conserved cell types with divergent features in human versus mouse cortex. Nature 573(7772):61–68. https://doi.org/10.1038/s41586-019-1506-7
Huang AY, Woo J, Sardar D, Lozzi B, Bosquez Huerta NA, Lin CJ et al (2020) Region-specific transcriptional control of astrocyte function oversees local circuit activities. Neuron 106(6):992-1008.e1009. https://doi.org/10.1016/j.neuron.2020.03.025
Ioannou MS, Jackson J, Sheu SH, Chang CL, Weigel AV, Liu H et al (2019) Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177(6):1522-1535.e1514. https://doi.org/10.1016/j.cell.2019.04.001
Jakovcevski I, Filipovic R, Mo Z, Rakic S, Zecevic N (2009) Oligodendrocyte development and the onset of myelination in the human fetal brain. Front Neuroanat 3:5. https://doi.org/10.3389/neuro.05.005.2009
Jiang J, Wang C, Qi R, Fu H, Ma Q (2020) scREAD: a single-cell RNA-seq database for Alzheimer’s disease. iScience 23(11):101769. https://doi.org/10.1016/j.isci.2020.101769
Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH et al (2021) Inference and analysis of cell-cell communication using cell chat. Nat Commun 12(1):1088. https://doi.org/10.1038/s41467-021-21246-9
John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J et al (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20(3):396–405. https://doi.org/10.1038/nn.4493
Jordao MJC, Sankowski R, Brendecke SM, Sagar, Locatelli G, Tai YH et al (2019) Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science. https://doi.org/10.1126/science.aat7554
Jorstad NL, Wilken MS, Grimes WN, Wohl SG, VandenBosch LS, Yoshimatsu T et al (2017) Stimulation of functional neuronal regeneration from Muller glia in adult mice. Nature 548(7665):103–107. https://doi.org/10.1038/nature23283
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20(11):4106–4114. https://doi.org/10.1128/mcb.20.11.4106-4114.2000
Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4):668–681. https://doi.org/10.1016/j.neuron.2010.09.009
Kantzer CG, Boutin C, Herzig ID, Wittwer C, Reiss S, Tiveron MC et al (2017) Anti-ACSA-2 defines a novel monoclonal antibody for prospective isolation of living neonatal and adult astrocytes. Glia 65(6):990–1004. https://doi.org/10.1002/glia.23140
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(7):1276-1290.e1217. https://doi.org/10.1016/j.cell.2017.05.018
Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M, Richardson WD (2006) Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci 9(2):173–179. https://doi.org/10.1038/nn1620
Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16(3):273–280. https://doi.org/10.1038/nn.3318
Konishi H, Okamoto T, Hara Y, Komine O, Tamada H, Maeda M et al (2020) Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction. EMBO J 39(22):e104464. https://doi.org/10.15252/embj.2020104464
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318. https://doi.org/10.1016/0166-2236(96)10049-7
Kucharova K, Stallcup WB (2018) Dissecting the multifactorial nature of demyelinating disease. Neural Regen Res 13(4):628–632. https://doi.org/10.4103/1673-5374.230281
Lashley T, Schott JM, Weston P, Murray CE, Wellington H, Keshavan A et al (2018) Molecular biomarkers of Alzheimer’s disease: progress and prospects. Dis Model Mech. https://doi.org/10.1242/dmm.031781
Lee Y, Messing A, Su M, Brenner M (2008) GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 56(5):481–493. https://doi.org/10.1002/glia.20622
Letelier J, de la Calle-Mustienes E, Pieretti J, Naranjo S, Maeso I, Nakamura T et al (2018) A conserved Shh cis-regulatory module highlights a common developmental origin of unpaired and paired fins. Nat Genet 50(4):504–509. https://doi.org/10.1038/s41588-018-0080-5
Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J et al (2019) Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-Cell RNA sequencing. Neuron 101(2):207-223.e210. https://doi.org/10.1016/j.neuron.2018.12.006
Li Y, He X, Kawaguchi R, Zhang Y, Wang Q, Monavarfeshani A et al (2020) Microglia-organized scar-free spinal cord repair in neonatal mice. Nature 587(7835):613–618. https://doi.org/10.1038/s41586-020-2795-6
Liddelow SA, Marsh SE, Stevens B (2020) Microglia and astrocytes in disease: dynamic duo or partners in crime? Trends Immunol 41(9):820–835. https://doi.org/10.1016/j.it.2020.07.006
Linnerbauer M, Wheeler MA, Quintana FJ (2020) Astrocyte crosstalk in CNS inflammation. Neuron 108(4):608–622. https://doi.org/10.1016/j.neuron.2020.08.012
Lu F, Chen Y, Zhao C, Wang H, He D, Xu L et al (2016) Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma. Cancer Cell 29(5):669–683. https://doi.org/10.1016/j.ccell.2016.03.027
Lundquist AJ, Parizher J, Petzinger GM, Jakowec MW (2019) Exercise induces region-specific remodeling of astrocyte morphology and reactive astrocyte gene expression patterns in male mice. J Neurosci Res 97(9):1081–1094. https://doi.org/10.1002/jnr.24430
Madore C, Yin Z, Leibowitz J, Butovsky O (2020) Microglia, lifestyle stress, and neurodegeneration. Immunity 52(2):222–240. https://doi.org/10.1016/j.immuni.2019.12.003
Mantzavinos V, Alexiou A (2017) Biomarkers for Alzheimer’s disease diagnosis. Curr Alzheimer Res 14(11):1149–1154. https://doi.org/10.2174/1567205014666170203125942
Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcao A, Xiao L et al (2016) Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 352(6291):1326–1329. https://doi.org/10.1126/science.aaf6463
Marques S, van Bruggen D, Vanichkina DP, Floriddia EM, Munguba H, Varemo L et al (2018) Transcriptional convergence of oligodendrocyte lineage progenitors during development. Dev Cell 46(4):504-517.e507. https://doi.org/10.1016/j.devcel.2018.07.005
Masuda T, Sankowski R, Staszewski O, Bottcher C, Amann L et al (2019) Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566(7744):388–392. https://doi.org/10.1038/s41586-019-0924-x
Mathys H, Adaikkan C, Gao F, Young JZ, Manet E, Hemberg M et al (2017) Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep 21(2):366–380. https://doi.org/10.1016/j.celrep.2017.09.039
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570(7761):332–337. https://doi.org/10.1038/s41586-019-1195-2
Mattugini N, Bocchi R, Scheuss V, Russo GL, Torper O, Lao CL, Gotz M (2019) Inducing different neuronal subtypes from astrocytes in the injured mouse cerebral cortex. Neuron 103(6):1086-1095.e1085. https://doi.org/10.1016/j.neuron.2019.08.009
Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M (1998) Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152(2):391–398
Michalski JP, Kothary R (2015) Oligodendrocytes in a nutshell. Front Cell Neurosci 9:340. https://doi.org/10.3389/fncel.2015.00340
Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93(3):421–443. https://doi.org/10.1016/j.pneurobio.2011.01.005
Mildner A, Huang H, Radke J, Stenzel W, Priller J (2017) P2Y12 receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases. Glia 65(2):375–387. https://doi.org/10.1002/glia.23097
Molofsky AV, Deneen B (2015) Astrocyte development: a guide for the perplexed. Glia 63(8):1320–1329. https://doi.org/10.1002/glia.22836
Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD et al (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26(9):891–907. https://doi.org/10.1101/gad.188326.112
Molofsky AV, Glasgow SM, Chaboub LS, Tsai HH, Murnen AT, Kelley KW et al (2013) Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 61(9):1518–1532. https://doi.org/10.1002/glia.22538
Morel L, Chiang MSR, Higashimori H, Shoneye T, Iyer LK, Yelick J et al (2017) Molecular and functional properties of regional astrocytes in the adult brain. J Neurosci 37(36):8706–8717. https://doi.org/10.1523/JNEUROSCI.3956-16.2017
Nagelhus EA, Ottersen OP (2013) Physiological roles of aquaporin-4 in brain. Physiol Rev 93(4):1543–1562. https://doi.org/10.1152/physrev.00011.2013
Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q et al (2021) Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets. Sci Adv. https://doi.org/10.1126/sciadv.abb5398
Niu J, Tsai HH, Hoi KK, Huang N, Yu G, Kim K et al (2019) Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation. Nat Neurosci 22(5):709–718. https://doi.org/10.1038/s41593-019-0369-4
Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7(2):136–144. https://doi.org/10.1038/nn1172
Noel F, Massenet-Regad L, Carmi-Levy I, Cappuccio A, Grandclaudon M, Trichot C et al (2021) Dissection of intercellular communication using the transcriptome-based framework ICELLNET. Nat Commun 12(1):1089. https://doi.org/10.1038/s41467-021-21244-x
Papalexi E, Satija R (2018) Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol 18(1):35–45. https://doi.org/10.1038/nri.2017.76
Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596–1609. https://doi.org/10.1016/j.cell.2013.11.030
Patel DC, Tewari BP, Chaunsali L, Sontheimer H (2019) Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci 20(5):282–297. https://doi.org/10.1038/s41583-019-0126-4
Penney J, Ralvenius WT, Tsai LH (2020) Modeling Alzheimer’s disease with iPSC-derived brain cells. Mol Psychiatry 25(1):148–167. https://doi.org/10.1038/s41380-019-0468-3
Philips T, Rothstein JD (2017) Oligodendroglia: metabolic supporters of neurons. J Clin Invest 127(9):3271–3280. https://doi.org/10.1172/JCI90610
Ravanelli AM, Appel B (2015) Motor neurons and oligodendrocytes arise from distinct cell lineages by progenitor recruitment. Genes Dev 29(23):2504–2515. https://doi.org/10.1101/gad.271312.115
Richardson WD, Smith HK, Sun T, Pringle NP, Hall A, Woodruff R (2000) Oligodendrocyte lineage and the motor neuron connection. Glia 29(2):136–142. https://doi.org/10.1002/(sici)1098-1136(20000115)29:2%3c136::aid-glia6%3e3.0.co;2-g
Richardson WD, Kessaris N, Pringle N (2006) Oligodendrocyte wars. Nat Rev Neurosci 7(1):11–18. https://doi.org/10.1038/nrn1826
Rosenberg AB, Roco CM, Muscat RA, Kuchina A, Sample P, Yao Z et al (2018) Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science 360(6385):176–182. https://doi.org/10.1126/science.aam8999
Rusakov DA (2015) Disentangling calcium-driven astrocyte physiology. Nat Rev Neurosci 16(4):226–233. https://doi.org/10.1038/nrn3878
Santello M, Toni N, Volterra A (2019) Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci 22(2):154–166. https://doi.org/10.1038/s41593-018-0325-8
Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388(10043):505–517. https://doi.org/10.1016/S0140-6736(15)01124-1
Sellers DL, Maris DO, Horner PJ (2009) Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci 29(20):6722–6733. https://doi.org/10.1523/JNEUROSCI.4538-08.2009
Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N et al (2015) Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci 18(12):1819–1831. https://doi.org/10.1038/nn.4160
Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156. https://doi.org/10.1038/nrn1326
Song HW, Foreman KL, Gastfriend BD, Kuo JS, Palecek SP, Shusta EV (2020) Transcriptomic comparison of human and mouse brain microvessels. Sci Rep 10(1):12358. https://doi.org/10.1038/s41598-020-69096-7
Spitzer SO, Sitnikov S, Kamen Y, Evans KA, Kronenberg-Versteeg D, Dietmann S et al (2019) Oligodendrocyte progenitor cells become regionally diverse and heterogeneous with age. Neuron 101(3):459-471.e455. https://doi.org/10.1016/j.neuron.2018.12.020
Srinivasan R, Lu TY, Chai H, Xu J, Huang BS, Golshani P et al (2016) New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron 92(6):1181–1195. https://doi.org/10.1016/j.neuron.2016.11.030
Sun LO, Mulinyawe SB, Collins HY, Ibrahim A, Li Q, Simon DJ et al (2018) Spatiotemporal control of CNS myelination by oligodendrocyte programmed cell death through the TFEB-PUMA axis. Cell 175(7):1811-1826.e1821. https://doi.org/10.1016/j.cell.2018.10.044
Svensson V, Vento-Tormo R, Teichmann SA (2018) Exponential scaling of single-cell RNA-seq in the past decade. Nat Protoc 13(4):599–604. https://doi.org/10.1038/nprot.2017.149
Tran AP, Warren PM, Silver J (2018) The biology of regeneration failure and success after spinal cord injury. Physiol Rev 98(2):881–917. https://doi.org/10.1152/physrev.00017.2017
Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H et al (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337(6092):358–362. https://doi.org/10.1126/science.1222381
van der Poel M, Ulas T, Mizee MR, Hsiao CC, Miedema SSM et al (2019) Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun 10(1):1139. https://doi.org/10.1038/s41467-019-08976-7
van Tilborg E, de Theije CGM, van Hal M, Wagenaar N, de Vries LS, Benders MJ et al (2018) Origin and dynamics of oligodendrocytes in the developing brain: implications for perinatal white matter injury. Glia 66(2):221–238. https://doi.org/10.1002/glia.23256
Vandebroek A, Yasui M (2020) Regulation of AQP4 in the central nervous system. Int J Mol Sci 21(5):1603. https://doi.org/10.3390/ijms21051603
Walker DG, Tang TM, Mendsaikhan A, Tooyama I, Serrano GE, Sue LI et al (2020) Patterns of expression of purinergic receptor P2RY12, a putative marker for non-activated microglia, in aged and Alzheimer’s disease brains. Int J Mol Sci 21(2):678. https://doi.org/10.3390/ijms21020678
Wang M, Roussos P, McKenzie A, Zhou X, Kajiwara Y, Brennand KJ et al (2016) Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease. Genome Med 8(1):104. https://doi.org/10.1186/s13073-016-0355-3
Wang W, Hu CK, Zeng A, Alegre D, Hu D, Gotting K et al (2020) Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates. Science. https://doi.org/10.1126/science.aaz3090
Wu W, Li Y, Wei Y, Bosco DB, Xie M, Zhao MG et al (2020) Microglial depletion aggravates the severity of acute and chronic seizures in mice. Brain Behav Immun 89:245–255. https://doi.org/10.1016/j.bbi.2020.06.028
Xing L, Yang T, Cui S, Chen G (2019) Connexin hemichannels in astrocytes: role in CNS disorders. Front Mol Neurosci 12:23. https://doi.org/10.3389/fnmol.2019.00023
Xu X, Stoyanova EI, Lemiesz AE, Xing J, Mash DC, Heintz N (2018) Species and cell-type properties of classically defined human and rodent neurons and glia. Elife. https://doi.org/10.7554/eLife.37551
Xu J, Zhang P, Huang Y, Zhou Y, Hou Y, Bekris L et al (2021) Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease. Genome Res. https://doi.org/10.1101/gr.272484.120
Yang T, Xing L, Yu W, Cai Y, Cui S, Chen G (2020) Astrocytic reprogramming combined with rehabilitation strategy improves recovery from spinal cord injury. FASEB J 34(11):15504–15515. https://doi.org/10.1096/fj.202001657RR
Yang HS, Onos KD, Choi K, Keezer KJ, Skelly DA, Carter GW, Howell GR (2021) Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease. Cell Rep 34(6):108739. https://doi.org/10.1016/j.celrep.2021.108739
Yao K, Gong GM, Fu ZX, Wang YQ, Zhang LZ, Li GC, Yang YM (2020) Synthesis and evaluation of cytocompatible alkyne-containing poly(beta-amino ester)-based hydrogels functionalized via click reaction. ACS Macro Lett 9(9):1391–1397. https://doi.org/10.1021/acsmacrolett.0c00545
Yu X, Nagai J, Khakh BS (2020) Improved tools to study astrocytes. Nat Rev Neurosci 21(3):121–138. https://doi.org/10.1038/s41583-020-0264-8
Zeisel A, Hochgerner H, Lonnerberg P, Johnsson A, Memic F, van der Zwan J et al (2018) Molecular architecture of the mouse nervous system. Cell 174(4):999-1014.e1022. https://doi.org/10.1016/j.cell.2018.06.021
Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20(5):588–594. https://doi.org/10.1016/j.conb.2010.06.005
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014
Zhang X, Wang R, Hu D, Sun X, Fujioka H, Lundberg K et al (2020) Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease. Sci Adv. https://doi.org/10.1126/sciadv.abb8680
Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR et al (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. https://doi.org/10.1038/s41591-019-0695-9
Zhuo L, Theis M, Alvarez-Maya I, Brenner M, Willecke K, Messing A (2001) hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31(2):85–94. https://doi.org/10.1002/gene.10008
Zonouzi M, Berger D, Jokhi V, Kedaigle A, Lichtman J, Arlotta P (2019) Individual oligodendrocytes show bias for inhibitory axons in the neocortex. Cell Rep 27(10):2799-2808.e2793. https://doi.org/10.1016/j.celrep.2019.05.018
Acknowledgements
We gratefully acknowledge the National Science Foundation of China (Grant No. 81701127 to XL, Grant No. 32000841 to SJ), the Municipal Health Commission of Nantong (Grant No. MA2020019 to QJ), and the Science and Technology Bureau of Nantong (Grant No. JC2020101 to QJ).
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Sun, J., Song, Y., Chen, Z. et al. Heterogeneity and Molecular Markers for CNS Glial Cells Revealed by Single-Cell Transcriptomics. Cell Mol Neurobiol 42, 2629–2642 (2022). https://doi.org/10.1007/s10571-021-01159-3
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DOI: https://doi.org/10.1007/s10571-021-01159-3