Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination

Jinchao Hou; Yingyue Zhou; Zhangying Cai; Marina Terekhova; Amanda Swain; Prabhakar S. Andhey; Rafaela M. Guimaraes; Alina Ulezko Antonova; Tian Qiu; Sanja Sviben; Gregory Strout; James A.J. Fitzpatrick; Yun Chen; Susan Gilfillan; Do Hyun Kim; Steven J. Van Dyken; Maxim N. Artyomov; Marco Colonna

doi:10.1016/j.celrep.2023.112293

Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination

Jinchao Hou, Yingyue Zhou, Zhangying Cai, Marina Terekhova, Amanda Swain, Prabhakar S. Andhey, Rafaela M. Guimaraes, Alina Ulezko Antonova, Tian Qiu, Sanja Sviben, Gregory Strout, James A.J. Fitzpatrick, Yun Chen, Susan Gilfillan, Do Hyun Kim, Steven J. Van Dyken, Maxim N. Artyomov, Marco Colonna

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB^hi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

Original language	English
Article number	112293
Journal	Cell Reports
Volume	42
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2023.112293
State	Published - Apr 25 2023

Keywords

CP: Neuroscience
IL-33
MAFB
TREM2
astrocytes
cuprizone
demyelination
microglia
oligodendrocytes
remyelination
single-nucleus RNA-seq

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10.1016/j.celrep.2023.112293

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Hou, J., Zhou, Y., Cai, Z., Terekhova, M., Swain, A., Andhey, P. S., Guimaraes, R. M., Ulezko Antonova, A., Qiu, T., Sviben, S., Strout, G., Fitzpatrick, J. A. J., Chen, Y., Gilfillan, S., Kim, D. H., Van Dyken, S. J., Artyomov, M. N., & Colonna, M. (2023). Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination. Cell Reports, 42(4), Article 112293. https://doi.org/10.1016/j.celrep.2023.112293

@article{4277ee473437438f8b27eddf49e4af5a,

title = "Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination",

abstract = "Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.",

keywords = "CP: Neuroscience, IL-33, MAFB, TREM2, astrocytes, cuprizone, demyelination, microglia, oligodendrocytes, remyelination, single-nucleus RNA-seq",

author = "Jinchao Hou and Yingyue Zhou and Zhangying Cai and Marina Terekhova and Amanda Swain and Andhey, {Prabhakar S.} and Guimaraes, {Rafaela M.} and {Ulezko Antonova}, Alina and Tian Qiu and Sanja Sviben and Gregory Strout and Fitzpatrick, {James A.J.} and Yun Chen and Susan Gilfillan and Kim, {Do Hyun} and {Van Dyken}, {Steven J.} and Artyomov, {Maxim N.} and Marco Colonna",

note = "Funding Information: We thank Tristan Q. Li, Simone Brioschi, and Vincent Peng for scientific discussions. We thank David M. Holtzman for providing the anti-APOE antibody. We acknowledge the Washington University Center for Cellular Imaging for assistance in imaging studies, supported by Washington University School of Medicine , the Children{\textquoteright}s Discovery Institute of University and St. Louis Children's Hospital ( CDI-CORE-2015-505 and CDI-CORE-2019-813 ), the Foundation for Barnes-Jewish Hospital ( 3770 ), the Washington University Diabetes Research Center ( DK020579 ), and the Alvin J. Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital ( CA091842 ). The Zeiss LSM880 microscope was purchased with support from the Office of Research Infrastructure Programs, National Institutes of Health , a part of the NIH Office of the Director ( OD021629 ). J.A.J.F. is supported by a Chan Zuckerberg Initiative Imaging Scientist award ( 2020-225726 ). R.M.G. is supported by the S{\~a}o Paulo Research Foundation ( FAPESP , 2021/10477-5 ). M.C. is supported by the NIH ( RF1 AG051485 , R21 AG059176 , and RF1 AG059082 ) and Cure Alzheimer's Fund . Graphical abstract and schematics were created with BioRender.com . Funding Information: We thank Tristan Q. Li, Simone Brioschi, and Vincent Peng for scientific discussions. We thank David M. Holtzman for providing the anti-APOE antibody. We acknowledge the Washington University Center for Cellular Imaging for assistance in imaging studies, supported by Washington University School of Medicine, the Children's Discovery Institute of University and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), the Foundation for Barnes-Jewish Hospital (3770), the Washington University Diabetes Research Center (DK020579), and the Alvin J. Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital (CA091842). The Zeiss LSM880 microscope was purchased with support from the Office of Research Infrastructure Programs, National Institutes of Health, a part of the NIH Office of the Director (OD021629). J.A.J.F. is supported by a Chan Zuckerberg Initiative Imaging Scientist award (2020-225726). R.M.G. is supported by the S{\~a}o Paulo Research Foundation (FAPESP, 2021/10477-5). M.C. is supported by the NIH (RF1 AG051485, R21 AG059176, and RF1 AG059082) and Cure Alzheimer's Fund. Graphical abstract and schematics were created with BioRender.com. J.H. Y.Z. and M.C. designed the study and interpreted the results. J.H. performed animal experiments. J.H. and A.S. prepared single nuclei suspension samples. J.H. Y.Z. P.S.A. M.T. A.U.A. and T.Q. performed bioinformatic analyses. J.H. conducted immunostaining, and Z.C. and R.M.G. performed quantification. Y.C. provided anti-APOE antibody. S.S. G.S. and J.A.J.F. performed EM sample preparation and imaging. S.G. bred Trem2−/− mice. D.-H.K. and S.J.V.D. provided Il1rl1−/− mice. M.N.A. provided guidance on bioinformatic analyses. J.H. Y.Z. S.G. and M.C. wrote and revised the manuscript with feedback from all authors. All authors approved the final version of the manuscript. M.C. is a member of the scientific advisory board of Vigil, receives research support from Vigil, and is a consultant for CST. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = apr,

day = "25",

doi = "10.1016/j.celrep.2023.112293",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

number = "4",

}

Hou, J, Zhou, Y, Cai, Z, Terekhova, M, Swain, A, Andhey, PS, Guimaraes, RM, Ulezko Antonova, A, Qiu, T, Sviben, S, Strout, G, Fitzpatrick, JAJ, Chen, Y, Gilfillan, S, Kim, DH, Van Dyken, SJ , Artyomov, MN & Colonna, M 2023, 'Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination', Cell Reports, vol. 42, no. 4, 112293. https://doi.org/10.1016/j.celrep.2023.112293

TY - JOUR

T1 - Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination

AU - Hou, Jinchao

AU - Zhou, Yingyue

AU - Cai, Zhangying

AU - Terekhova, Marina

AU - Swain, Amanda

AU - Andhey, Prabhakar S.

AU - Guimaraes, Rafaela M.

AU - Ulezko Antonova, Alina

AU - Qiu, Tian

AU - Sviben, Sanja

AU - Strout, Gregory

AU - Fitzpatrick, James A.J.

AU - Chen, Yun

AU - Gilfillan, Susan

AU - Kim, Do Hyun

AU - Van Dyken, Steven J.

AU - Artyomov, Maxim N.

AU - Colonna, Marco

N1 - Funding Information: We thank Tristan Q. Li, Simone Brioschi, and Vincent Peng for scientific discussions. We thank David M. Holtzman for providing the anti-APOE antibody. We acknowledge the Washington University Center for Cellular Imaging for assistance in imaging studies, supported by Washington University School of Medicine , the Children’s Discovery Institute of University and St. Louis Children's Hospital ( CDI-CORE-2015-505 and CDI-CORE-2019-813 ), the Foundation for Barnes-Jewish Hospital ( 3770 ), the Washington University Diabetes Research Center ( DK020579 ), and the Alvin J. Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital ( CA091842 ). The Zeiss LSM880 microscope was purchased with support from the Office of Research Infrastructure Programs, National Institutes of Health , a part of the NIH Office of the Director ( OD021629 ). J.A.J.F. is supported by a Chan Zuckerberg Initiative Imaging Scientist award ( 2020-225726 ). R.M.G. is supported by the São Paulo Research Foundation ( FAPESP , 2021/10477-5 ). M.C. is supported by the NIH ( RF1 AG051485 , R21 AG059176 , and RF1 AG059082 ) and Cure Alzheimer's Fund . Graphical abstract and schematics were created with BioRender.com . Funding Information: We thank Tristan Q. Li, Simone Brioschi, and Vincent Peng for scientific discussions. We thank David M. Holtzman for providing the anti-APOE antibody. We acknowledge the Washington University Center for Cellular Imaging for assistance in imaging studies, supported by Washington University School of Medicine, the Children's Discovery Institute of University and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), the Foundation for Barnes-Jewish Hospital (3770), the Washington University Diabetes Research Center (DK020579), and the Alvin J. Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital (CA091842). The Zeiss LSM880 microscope was purchased with support from the Office of Research Infrastructure Programs, National Institutes of Health, a part of the NIH Office of the Director (OD021629). J.A.J.F. is supported by a Chan Zuckerberg Initiative Imaging Scientist award (2020-225726). R.M.G. is supported by the São Paulo Research Foundation (FAPESP, 2021/10477-5). M.C. is supported by the NIH (RF1 AG051485, R21 AG059176, and RF1 AG059082) and Cure Alzheimer's Fund. Graphical abstract and schematics were created with BioRender.com. J.H. Y.Z. and M.C. designed the study and interpreted the results. J.H. performed animal experiments. J.H. and A.S. prepared single nuclei suspension samples. J.H. Y.Z. P.S.A. M.T. A.U.A. and T.Q. performed bioinformatic analyses. J.H. conducted immunostaining, and Z.C. and R.M.G. performed quantification. Y.C. provided anti-APOE antibody. S.S. G.S. and J.A.J.F. performed EM sample preparation and imaging. S.G. bred Trem2−/− mice. D.-H.K. and S.J.V.D. provided Il1rl1−/− mice. M.N.A. provided guidance on bioinformatic analyses. J.H. Y.Z. S.G. and M.C. wrote and revised the manuscript with feedback from all authors. All authors approved the final version of the manuscript. M.C. is a member of the scientific advisory board of Vigil, receives research support from Vigil, and is a consultant for CST. Publisher Copyright: © 2023 The Authors

PY - 2023/4/25

Y1 - 2023/4/25

N2 - Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

AB - Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

KW - CP: Neuroscience

KW - IL-33

KW - MAFB

KW - TREM2

KW - astrocytes

KW - cuprizone

KW - demyelination

KW - microglia

KW - oligodendrocytes

KW - remyelination

KW - single-nucleus RNA-seq

UR - http://www.scopus.com/inward/record.url?scp=85150769008&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112293

DO - 10.1016/j.celrep.2023.112293

M3 - Article

C2 - 36952346

AN - SCOPUS:85150769008

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 112293

ER -

Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination

Abstract

Keywords

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