Single-cell transcriptomics of human traumatic brain injury reveals activation of endogenous retroviruses in oligodendroglia
Raquel Garza,
Yogita Sharma,
Diahann A.M. Atacho,
Arun Thiruvalluvan,
Sami Abu Hamdeh,
Marie E. Jönsson,
Vivien Horvath,
Anita Adami,
Martin Ingelsson,
Patric Jern,
Molly Gale Hammell,
Elisabet Englund,
Agnete Kirkeby,
Johan Jakobsson,
Niklas Marklund
Affiliations
Raquel Garza
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Yogita Sharma
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Diahann A.M. Atacho
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Arun Thiruvalluvan
Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
Sami Abu Hamdeh
Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
Marie E. Jönsson
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Vivien Horvath
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Anita Adami
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Martin Ingelsson
Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada; Krembil Brain Institute, University Health Network, Toronto, ON, Canada
Patric Jern
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Molly Gale Hammell
Institute for Systems Genetics, Department of Neuroscience and Physiology, NYU Langone Health, New York, NY 10016, USA; Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10003, USA
Elisabet Englund
Department of Clinical Sciences Lund, Division of Pathology, Lund University, Lund, Sweden
Agnete Kirkeby
Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark; Department of Experimental Medical Science, Wallenberg Center for Molecular Medicine and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
Johan Jakobsson
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden; Corresponding author
Niklas Marklund
Department of Clinical Sciences Lund, Neurosurgery, Lund University, Skåne University Hospital, Lund, Sweden
Summary: Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.
