Phenotypic and spatial heterogeneity of brain myeloid cells after stroke is associated with cell ontogeny, tissue damage, and brain connectivity
Anirudh Patir,
Jack Barrington,
Stefan Szymkowiak,
Gaia Brezzo,
Dana Straus,
Alessio Alfieri,
Lucas Lefevre,
Zhaoyuan Liu,
Florent Ginhoux,
Neil C. Henderson,
Karen Horsburgh,
Prakash Ramachandran,
Barry W. McColl
Affiliations
Anirudh Patir
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Jack Barrington
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Stefan Szymkowiak
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Gaia Brezzo
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Dana Straus
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Alessio Alfieri
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Lucas Lefevre
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Zhaoyuan Liu
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Florent Ginhoux
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
Neil C. Henderson
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4TJ, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
Karen Horsburgh
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
Prakash Ramachandran
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4TJ, UK
Barry W. McColl
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; Corresponding author
Summary: Acute stroke triggers extensive changes to myeloid immune cell populations in the brain that may be targets for limiting brain damage and enhancing repair. Immunomodulatory approaches will be most effective with precise manipulation of discrete myeloid cell phenotypes in time and space. Here, we investigate how stroke alters mononuclear myeloid cell composition and phenotypes at single-cell resolution and key spatial patterns. Our results show that multiple reactive microglial states and monocyte-derived populations contribute to an extensive myeloid cell repertoire in post-stroke brains. We identify important overlaps and distinctions among different cell types/states that involve ontogeny- and spatial-related properties. Notably, brain connectivity with infarcted tissue underpins the pattern of local and remote altered cell accumulation and reactivity. Our discoveries suggest a global but anatomically governed brain myeloid cell response to stroke that comprises diverse phenotypes arising through intrinsic cell ontogeny factors interacting with exposure to spatially organized brain damage and neuro-axonal cues.
