Single-Cell Transcriptomics Analysis Reveals the Promotion of Mitochondrial Hyperactive Microglial Subpopulations by CSF1R following Stroke

Abstract

Abstract Stroke is a medical emergency that occurs due to interruption or reduction of the blood supply to the brain, which results in brain tissue damage. Despite mitochondria are damaged to a certain extent after cells are subjected to oxygen/sugar deprivation following stroke, clinical data have not demonstrated mitochondrial damage aggravates the progression of stroke. In the present study, single-cell RNA sequencing (scRNA-seq) data of 29,388 cells from the hippocampus of normal mice and those with ischemic or hemorrhagic stroke were obtained and further analyzed. Our data reveal extensive heterogeneity among immune cells, with microglia exhibiting distinct transcriptomic signatures. In-depth bioinformatics analysis identified the mitochondrial leucine-tRNA synthetase 2 (Lars2) as being aberrantly expressed in multiple cell types. Additionally, stroke-specific microglial subpopulations exhibited similar expression patterns to those of disease-associated microglia (DAM). The Csf1-Csf1r pathway was highly activated in microglia during the autocrine process following stroke, and Csf1r is highly expressed in microglia and macrophages in the central nervous system, suggesting Csf1r promotes the subpopulation of microglia with highly active mitochondria following stroke. Our results implied that blockade of the Csf1r signaling pathway may have therapeutic significance in neuroinflammatory diseases such as stroke. These findings provide new insights into cell subtype diversity and molecular characteristics following brain injury from the perspective of microglia and mitochondria.