Abstract
Astrocytes are the most plentiful cell type in the central nervous system (CNS) and perform complicated functions in health and disease. It is obvious that different astrocyte subpopulations, or activation states, are relevant with specific genomic programs and functions. In recent years, the emergence of new technologies such as single-cell RNA sequencing (scRNA-seq) has made substantial advance in the characterization of astrocyte heterogeneity, astrocyte developmental trajectory, and its role in CNS diseases which has had a significant impact on neuroscience. In this review, we present an overview of astrocyte development, heterogeneity, and its essential role in the physiological and pathological environments of the CNS. We focused on the critical role of single-cell sequencing in revealing astrocyte development, heterogeneity, and its role in different CNS diseases.
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References
Al-Dalahmah O et al (2020) Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol Commun 8(1):19
Anderson MA, Ao Y, Sofroniew MV (2014) Heterogeneity of reactive astrocytes. Neurosci Lett 565:9–23
Babikir H et al (2021) ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma. Genome Biol 22(1):311
Baecher-Allan C, Kaskow BJ, Weiner HL (2018) Multiple sclerosis: mechanisms and immunotherapy. Neuron 97(4):742–768
Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60(3):430–440
Batiuk MY et al (2020) Identification of region-specific astrocyte subtypes at single cell resolution. Nat Commun 11(1):1220
Bayraktar OA et al (2014) Astrocyte development and heterogeneity. Cold Spring Harb Perspect Biol 7(1):a020362
Bayraktar OA 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
Beckervordersandforth R et al (2010) In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell 7(6):744–758
Beitz JM (2014) Parkinson’s disease: a review. Front Biosci (schol Ed) 6(1):65–74
Blanco-Suárez E, Caldwell AL, Allen NJ (2017) Role of astrocyte-synapse interactions in CNS disorders. J Physiol 595(6):1903–1916
Boisvert MM et al (2018) The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22(1):269–285
Bradford J et al (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A 106(52):22480–22485
Brat DJ et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372(26):2481–2498
Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275:305–315
Chaboub LS, Deneen B (2012) Developmental origins of astrocyte heterogeneity: the final frontier of CNS development. Dev Neurosci 34(5):379–388
Chai H et al (2017) Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95(3):531-549.e9
Chen G, Ning B, Shi T (2019) Single-cell RNA-seq technologies and related computational data analysis. Front Genet 10:317
Chen W et al (2020) Single cell omics: from assay design to biomedical application. Biotechnol J 15(1):e1900262
Chia R, Chiò A, Traynor BJ (2018) Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 17(1):94–102
Christopherson KS et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433
Clarke LE, Barres BA (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14(5):311–321
Escartin C, Guillemaud O, Carrillo-de Sauvage MA (2019) Questions and (some) answers on reactive astrocytes. Glia 67(12):2221–2247
Escartin C et al (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 24(3):312–325
Farrell JA et al (2018) Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science 360(6392):eaar3131
Gao S (2018) Data analysis in single-cell transcriptome sequencing. Methods Mol Biol 1754:311–326
Garwood CJ et al (2017) Review: astrocytes in Alzheimer’s disease and other age-associated dementias: a supporting player with a central role. Neuropathol Appl Neurobiol 43(4):281–298
Ge WP et al (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484(7394):376–380
Giladi A, Amit I (2018) Single-cell genomics: a stepping stone for future immunology discoveries. Cell 172(1–2):14–21
Giovannoni F, Quintana FJ (2020) The role of astrocytes in CNS inflammation. Trends Immunol 41(9):805–819
Goldman JE (1995) Lineage, migration, and fate determination of postnatal subventricular zone cells in the mammalian CNS. J Neurooncol 24(1):61–64
Grosche A et al (2013) Versatile and simple approach to determine astrocyte territories in mouse neocortex and hippocampus. PLoS ONE 8(7):e69143
Grubman A 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
Guillamón-Vivancos T, Gómez-Pinedo U, Matías-Guiu J (2015) Astrocytes in neurodegenerative diseases (I): function and molecular description. Neurologia 30(2):119–129
Gulati GS et al (2020) Single-cell transcriptional diversity is a hallmark of developmental potential. Science 367(6476):405–411
Gupta RK, Kuznicki J (2020) Biological and medical importance of cellular heterogeneity deciphered by single-cell RNA sequencing. Cells 9(8):1751
Habib N et al (2020) Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci 23:701–706
Hasel P et al (2021) Neuroinflammatory astrocyte subtypes in the mouse brain. Nat Neurosci 24(10):1475–1487
Hedlund E, Deng Q (2018) Single-cell RNA sequencing: technical advancements and biological applications. Mol Aspects Med 59:36–46
Hu X et al (2016) Heterogeneous astrocytes: active players in CNS. Brain Res Bull 125:1–18
Huang X et al (2018) High throughput single cell RNA sequencing, bioinformatics analysis and applications. Adv Exp Med Biol 1068:33–43
Jacobsen CT, Miller RH (2003) Control of astrocyte migration in the developing cerebral cortex. Dev Neurosci 25(2–4):207–216
Jha MK, Morrison BM (2020) Lactate transporters mediate glia-neuron metabolic crosstalk in homeostasis and disease. Front Cell Neurosci 14:589582
Kaminska B, Ochocka N, Segit P (2021) Single-cell omics in dissecting immune microenvironment of malignant gliomas-challenges and perspectives. Cells 10(9):2264
Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18(7):942–952
Kucukdereli H et al (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci U S A 108(32):E440–E449
Lanjakornsiripan D et al (2018) Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers. Nat Commun 9(1):1623
Li C et al (2011) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8(1):67–80
Li Q et al (2019) Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101(2):207-223.e10
Linnerbauer M, Rothhammer V (2020) Protective functions of reactive astrocytes following central nervous system insult. Front Immunol 11:573256
Linnerbauer M, Wheeler MA, Quintana FJ (2020) Astrocyte crosstalk in CNS inflammation. Neuron 108(4):608–622
Liu W et al (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
Malatesta P et al (2003) Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37(5):751–764
Maniatis S et al (2019) Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science 364(6435):89–93
Marshall CA, Goldman JE (2002) Subpallial dlx2-expressing cells give rise to astrocytes and oligodendrocytes in the cerebral cortex and white matter. J Neurosci 22(22):9821–9830
Mathys H et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570(7761):332–337
Matyash V, Kettenmann H (2010) Heterogeneity in astrocyte morphology and physiology. Brain Res Rev 63(1–2):2–10
Miao Z et al (2020) Putative cell type discovery from single-cell gene expression data. Nat Methods 17(6):621–628
Mizrak D et al (2019) Single-cell analysis of regional differences in adult V-SVZ neural stem cell lineages. Cell Rep 26(2):394-406.e5
Molofsky AV, Deneen B (2015) Astrocyte development: a guide for the perplexed. Glia 63(8):1320–1329
Molofsky AV et al (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26(9):891–907
Montgomery DL (1994) Astrocytes: form, functions, and roles in disease. Vet Pathol 31(2):145–167
Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23–45
Olsen TK, Baryawno N (2018) Introduction to single-cell RNA sequencing. Curr Protoc Mol Biol 122(1):e57
Ono K et al (2008) Regional- and temporal-dependent changes in the differentiation of Olig2 progenitors in the forebrain, and the impact on astrocyte development in the dorsal pallium. Dev Biol 320(2):456–468
Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94(4):1077–1098
Pelvig DP et al (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29(11):1754–1762
Powell EM, Geller HM (1999) Dissection of astrocyte-mediated cues in neuronal guidance and process extension. Glia 26(1):73–83
Rodríguez-Arellano JJ et al (2016) Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323:170–182
Rusnakova V et al (2013) Heterogeneity of astrocytes: from development to injury—single cell gene expression. PLoS ONE 8(8):e69734
Sanmarco LM et al (2021) Gut-licensed IFNγ(+) NK cells drive LAMP1(+)TRAIL(+) anti-inflammatory astrocytes. Nature 590(7846):473–479
Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist 20(2):160–172
Sofroniew MV (2020) Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol 41(9):758–770
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35
Ståhlberg A et al (2011) Defining cell populations with single-cell gene expression profiling: correlations and identification of astrocyte subpopulations. Nucleic Acids Res 39(4):e24
Stubbington MJT et al (2017) Single-cell transcriptomics to explore the immune system in health and disease. Science 358(6359):58–63
Tanay A, Regev A (2017) Scaling single-cell genomics from phenomenology to mechanism. Nature 541(7637):331–338
Theis M, Giaume C (2012) Connexin-based intercellular communication and astrocyte heterogeneity. Brain Res 1487:88–98
Tiklová K et al (2020) Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease. Nat Commun 11(1):2434
Tong X et al (2014) Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci 17(5):694–703
Tsai HH et al (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337(6092):358–362
Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98(1):239–389
von Bartheld CS, Bahney J, Herculano-Houzel S (2016) The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol 524(18):3865–3895
Wang M et al (2011) Neuronal basis of age-related working memory decline. Nature 476(7359):210–213
Wheeler MA et al (2020) MAFG-driven astrocytes promote CNS inflammation. Nature 578(7796):593–599
Xie Y et al (2021) Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing. JCI Insight 6(15):e150861
Yang Y, Jackson R (2019) Astrocyte identity: evolutionary perspectives on astrocyte functions and heterogeneity. Curr Opin Neurobiol 56:40–46
Yeh TH et al (2009) Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation. Glia 57(11):1239–1249
Yoshimura Y, Dantzker JL, Callaway EM (2005) Excitatory cortical neurons form fine-scale functional networks. Nature 433(7028):868–873
Yu X, Nagai J, Khakh BS (2020) Improved tools to study astrocytes. Nat Rev Neurosci 21(3):121–138
Zamboni M et al (2020) A Widespread neurogenic potential of neocortical astrocytes is induced by injury. Cell Stem Cell 27(4):605-617.e5
Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20(5):588–594
Zhou B, Zuo YX, Jiang RT (2019) Astrocyte morphology: diversity, plasticity, and role in neurological diseases. CNS Neurosci Ther 25(6):665–673
Zhu X, Bergles DE, Nishiyama A (2008) NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 135(1):145–157
Ziegenhain C et al (2017) Comparative analysis of single-cell RNA sequencing methods. Mol Cell 65(4):631-643.e4
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This study was supported by the Chinese National Natural Science Foundation (Grant Nos. 82271199, 31970771, 82071396), the Shaanxi Provincial Key R&D Foundation (Grant No. 2021ZDLSF03-09), the Fundamental Research Funds for the Central Universities (Grant Nos. GK202201013, GK202202006).
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XL, YZ: participated in the conception and revision of the article. M-YG, J-QW, JH, and RG: collected and collated literatures. M-YG, and J-QW: wrote the manuscript and made diagrams with feedback from all authors. XL, and YZ: cosupervised the study and revised the paper. All authors read and approved the final manuscript.
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Gao, MY., Wang, JQ., He, J. et al. Single-Cell RNA-Sequencing in Astrocyte Development, Heterogeneity, and Disease. Cell Mol Neurobiol 43, 3449–3464 (2023). https://doi.org/10.1007/s10571-023-01397-7
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DOI: https://doi.org/10.1007/s10571-023-01397-7