Identification of Region-specific Astrocyte Subtypes at Single Cell Resolution

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Mar 7

PMID 32139688

Citations 327

Authors

Mykhailo Y Batiuk

Araks Martirosyan

Jerome Wahis

Filip de Vin

Catherine Marneffe

Carola Kusserow

Jordan Koeppen

Joao Filipe Viana

Joao Filipe Oliveira

Thierry Voet

Chris P Ponting

T Grant Belgard

Matthew G Holt

Affiliations

Soon will be listed here.

Abstract

Astrocytes, a major cell type found throughout the central nervous system, have general roles in the modulation of synapse formation and synaptic transmission, blood-brain barrier formation, and regulation of blood flow, as well as metabolic support of other brain resident cells. Crucially, emerging evidence shows specific adaptations and astrocyte-encoded functions in regions, such as the spinal cord and cerebellum. To investigate the true extent of astrocyte molecular diversity across forebrain regions, we used single-cell RNA sequencing. Our analysis identifies five transcriptomically distinct astrocyte subtypes in adult mouse cortex and hippocampus. Validation of our data in situ reveals distinct spatial positioning of defined subtypes, reflecting the distribution of morphologically and physiologically distinct astrocyte populations. Our findings are evidence for specialized astrocyte subtypes between and within brain regions. The data are available through an online database (https://holt-sc.glialab.org/), providing a resource on which to base explorations of local astrocyte diversity and function in the brain.

Citing Articles

Astrocyte heterogeneity reveals region-specific astrogenesis in the white matter.

Bocchi R, Thorwirth M, Simon-Ebert T, Koupourtidou C, Clavreul S, Kolf K Nat Neurosci. 2025; 28(3):457-469.

PMID: 39994409 PMC: 11893471. DOI: 10.1038/s41593-025-01878-6.

Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions.

Yang J, Agrawal K, Stanley 3rd J, Stanley J, Li R, Jacobs N bioRxiv. 2025; .

PMID: 39975288 PMC: 11839123. DOI: 10.1101/2025.02.05.636707.

Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer's Disease.

Lee E, Chang Y Cells. 2025; 14(3).

PMID: 39936960 PMC: 11817173. DOI: 10.3390/cells14030168.

Astrocyte-Secreted Lcn2 Modulates Dendritic Spine Morphology.

Doliwa M, Kuzniewska B, Nader K, Reniewicz P, Kaczmarek L, Michaluk P Cells. 2025; 14(3).

PMID: 39936951 PMC: 11817088. DOI: 10.3390/cells14030159.

A single-cell transcriptome analysis reveals astrocyte heterogeneity and identifies CHI3L1 as a diagnostic biomarker in Parkinson's disease.

Gong Z, Guo D, Lin Y, Liu Z, Lv M, Liu X Heliyon. 2025; 11(3):e42051.

PMID: 39931480 PMC: 11808505. DOI: 10.1016/j.heliyon.2025.e42051.

References

Zeisel A, Munoz-Manchado A, Codeluppi S, Lonnerberg P, La Manno G, Jureus A . Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015; 347(6226):1138-42. DOI: 10.1126/science.aaa1934. View

Grosche A, Grosche J, Tackenberg M, Scheller D, Gerstner G, Gumprecht A . Versatile and simple approach to determine astrocyte territories in mouse neocortex and hippocampus. PLoS One. 2013; 8(7):e69143. PMC: 3720564. DOI: 10.1371/journal.pone.0069143. View

Morel L, Chiang M, Higashimori H, Shoneye T, Iyer L, Yelick J . Molecular and Functional Properties of Regional Astrocytes in the Adult Brain. J Neurosci. 2017; 37(36):8706-8717. PMC: 5588463. DOI: 10.1523/JNEUROSCI.3956-16.2017. View

Boisvert M, Erikson G, Shokhirev M, Allen N . The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Rep. 2018; 22(1):269-285. PMC: 5783200. DOI: 10.1016/j.celrep.2017.12.039. View

Kelley K, Nakao-Inoue H, Molofsky A, Oldham M . Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes. Nat Neurosci. 2018; 21(9):1171-1184. PMC: 6192711. DOI: 10.1038/s41593-018-0216-z. View

Costa M, Kessaris N, Richardson W, Gotz M, Hedin-Pereira C . The marginal zone/layer I as a novel niche for neurogenesis and gliogenesis in developing cerebral cortex. J Neurosci. 2007; 27(42):11376-88. PMC: 6673031. DOI: 10.1523/JNEUROSCI.2418-07.2007. View

Beckervordersandforth R, Tripathi P, Ninkovic J, Bayam E, Lepier A, Stempfhuber B . In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell. 2010; 7(6):744-58. DOI: 10.1016/j.stem.2010.11.017. View

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

Nimmerjahn A, Kirchhoff F, Kerr J, Helmchen F . Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nat Methods. 2005; 1(1):31-7. DOI: 10.1038/nmeth706. View

10.

Khakh B, Sofroniew M . Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015; 18(7):942-52. PMC: 5258184. DOI: 10.1038/nn.4043. View

11.

Verkhratsky A, Nedergaard M . Physiology of Astroglia. Physiol Rev. 2018; 98(1):239-389. PMC: 6050349. DOI: 10.1152/physrev.00042.2016. View

12.

Allen N, Lyons D . Glia as architects of central nervous system formation and function. Science. 2018; 362(6411):181-185. PMC: 6292669. DOI: 10.1126/science.aat0473. View

13.

Itoh N, Itoh Y, Tassoni A, Ren E, Kaito M, Ohno A . Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc Natl Acad Sci U S A. 2017; 115(2):E302-E309. PMC: 5777065. DOI: 10.1073/pnas.1716032115. View

14.

Takata N, Hirase H . Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo. PLoS One. 2008; 3(6):e2525. PMC: 2424136. DOI: 10.1371/journal.pone.0002525. View

15.

Lein E, Hawrylycz M, Ao N, Ayres M, Bensinger A, Bernard A . Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2006; 445(7124):168-76. DOI: 10.1038/nature05453. View

16.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

17.

Saunders A, Macosko E, Wysoker A, Goldman M, Krienen F, de Rivera H . Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain. Cell. 2018; 174(4):1015-1030.e16. PMC: 6447408. DOI: 10.1016/j.cell.2018.07.028. View

18.

Blanco-Suarez E, Liu T, Kopelevich A, Allen N . Astrocyte-Secreted Chordin-like 1 Drives Synapse Maturation and Limits Plasticity by Increasing Synaptic GluA2 AMPA Receptors. Neuron. 2018; 100(5):1116-1132.e13. PMC: 6382071. DOI: 10.1016/j.neuron.2018.09.043. View

19.

Zeisel A, Hochgerner H, Lonnerberg P, Johnsson A, Memic F, van der Zwan J . Molecular Architecture of the Mouse Nervous System. Cell. 2018; 174(4):999-1014.e22. PMC: 6086934. DOI: 10.1016/j.cell.2018.06.021. View

20.

Ben Haim L, Rowitch D . Functional diversity of astrocytes in neural circuit regulation. Nat Rev Neurosci. 2016; 18(1):31-41. DOI: 10.1038/nrn.2016.159. View