Single-cell Transcriptomic Analysis of the Immune Cell Landscape in the Aged Mouse Brain After Ischemic Stroke

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2022 Apr 8

PMID 35392936

Authors

Xuan Li

Jingjun Lyu

Ran Li

Vaibhav Jain

Yuntian Shen

Angela Del Aguila

Ulrike Hoffmann

Huaxin Sheng

Wei Yang

Affiliations

Soon will be listed here.

Abstract

Background: Ischemic stroke is a medical emergency that primarily affects the elderly. A complex immune response in the post-stroke brain constitutes a key component of stroke pathophysiology. This study aimed to determine how stroke affects immune cell populations in the aged brain based on molecular profiles of individual cells.

Methods: Single-cell RNA sequencing and a new transient ischemic stroke mouse model with late reperfusion were used.

Results: We generated, for the first time, a composite picture of immune cell populations in the stroke aged brain at single-cell resolution. We discovered at least 6 microglial subsets in the stroke aged brain, including a potentially stroke-specific subtype. Moreover, we identified major cell subpopulations formed by infiltrated myeloid cells after stroke, and revealed their unique molecular profiles.

Conclusions: This study provided the first scRNA-seq data set for immune cells in the stroke aged brain, and offered novel insights into post-stroke immune cell heterogeneity.

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References

Jayaraj R, Azimullah S, Beiram R, Jalal F, Rosenberg G . Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019; 16(1):142. PMC: 6617684. DOI: 10.1186/s12974-019-1516-2. View

Grieshaber-Bouyer R, Radtke F, Cunin P, Stifano G, Levescot A, Vijaykumar B . The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments. Nat Commun. 2021; 12(1):2856. PMC: 8129206. DOI: 10.1038/s41467-021-22973-9. View

Zera K, Buckwalter M . The Local and Peripheral Immune Responses to Stroke: Implications for Therapeutic Development. Neurotherapeutics. 2020; 17(2):414-435. PMC: 7283378. DOI: 10.1007/s13311-020-00844-3. View

Mendiola A, Ryu J, Bardehle S, Meyer-Franke A, Ang K, Wilson C . Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation. Nat Immunol. 2020; 21(5):513-524. PMC: 7523413. DOI: 10.1038/s41590-020-0654-0. View

Fury W, Park K, Wu Z, Kim E, Woo M, Bai Y . Sustained Increases in Immune Transcripts and Immune Cell Trafficking During the Recovery of Experimental Brain Ischemia. Stroke. 2020; 51(8):2514-2525. PMC: 7815290. DOI: 10.1161/STROKEAHA.120.029440. View

Felger J, Abe T, Kaunzner U, Gottfried-Blackmore A, Gal-Toth J, McEwen B . Brain dendritic cells in ischemic stroke: time course, activation state, and origin. Brain Behav Immun. 2009; 24(5):724-37. PMC: 2885548. DOI: 10.1016/j.bbi.2009.11.002. View

Mrdjen D, Pavlovic A, Hartmann F, Schreiner B, Utz S, Leung B . High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity. 2018; 48(2):380-395.e6. DOI: 10.1016/j.immuni.2018.01.011. View

Zhang S, Phan T, Sobey C . Targeting the Immune System for Ischemic Stroke. Trends Pharmacol Sci. 2020; 42(2):96-105. DOI: 10.1016/j.tips.2020.11.010. View

Ransohoff R . A polarizing question: do M1 and M2 microglia exist?. Nat Neurosci. 2016; 19(8):987-91. DOI: 10.1038/nn.4338. View

10.

Chu H, Kim H, Lee S, Moore J, Chan C, Vinh A . Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia. J Cereb Blood Flow Metab. 2013; 34(3):450-9. PMC: 3948121. DOI: 10.1038/jcbfm.2013.217. View

11.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

12.

Wang S, de Fabritus L, Kumar P, Werner Y, Ma M, Li D . Brain endothelial CXCL12 attracts protective natural killer cells during ischemic stroke. J Neuroinflammation. 2023; 20(1):8. PMC: 9835334. DOI: 10.1186/s12974-023-02689-x. View

13.

Hammond T, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A . Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity. 2018; 50(1):253-271.e6. PMC: 6655561. DOI: 10.1016/j.immuni.2018.11.004. View

14.

Golomb S, Guldner I, Zhao A, Wang Q, Palakurthi B, Aleksandrovic E . Multi-modal Single-Cell Analysis Reveals Brain Immune Landscape Plasticity during Aging and Gut Microbiota Dysbiosis. Cell Rep. 2020; 33(9):108438. PMC: 7737488. DOI: 10.1016/j.celrep.2020.108438. View

15.

Ochocka N, Segit P, Walentynowicz K, Wojnicki K, Cyranowski S, Swatler J . Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages. Nat Commun. 2021; 12(1):1151. PMC: 7895824. DOI: 10.1038/s41467-021-21407-w. View

16.

Zheng K, Lin L, Jiang W, Chen L, Zhang X, Zhang Q . Single-cell RNA-seq reveals the transcriptional landscape in ischemic stroke. J Cereb Blood Flow Metab. 2021; 42(1):56-73. PMC: 8721774. DOI: 10.1177/0271678X211026770. View

17.

Jordao M, Sankowski R, Brendecke S, Sagar , Locatelli G, Tai Y . Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science. 2019; 363(6425). DOI: 10.1126/science.aat7554. View

18.

Iadecola C, Buckwalter M, Anrather J . Immune responses to stroke: mechanisms, modulation, and therapeutic potential. J Clin Invest. 2020; 130(6):2777-2788. PMC: 7260029. DOI: 10.1172/JCI135530. View

19.

Shi L, Sun Z, Su W, Xu F, Xie D, Zhang Q . Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity. 2021; 54(7):1527-1542.e8. PMC: 8282725. DOI: 10.1016/j.immuni.2021.04.022. View

20.

Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski N, Gautier E . Sall1 is a transcriptional regulator defining microglia identity and function. Nat Immunol. 2016; 17(12):1397-1406. DOI: 10.1038/ni.3585. View