Single‐nucleus transcriptome analysis reveals disease‐ and regeneration‐associated endothelial cells in white matter vascular dementia

• Published in: Journal of cellular and molecular medicine Vol. 26; no. 11; pp. 3183 - 3195
• Main Authors: Mitroi, Daniel N., Tian, Min, Kawaguchi, Riki, Lowry, William E., Carmichael, S. Thomas
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2022; John Wiley and Sons Inc
• Subjects: Alzheimer's disease; Angiogenesis; Antibodies; Apoptosis; Axon sprouting; Brain; Brain - metabolism; Cell death; Dementia; Dementia disorders; Dementia, Vascular - genetics; Dementia, Vascular - pathology; disease‐associated endothelial cells; Endothelial cells; Endothelial Cells - metabolism; Gene expression; Gene Expression Profiling; Genomes; Genomics; Glial stem cells; Homogenization; Humans; Immune response; Ischemia; Myelination; Original; Progenitor cells; Protein folding; Regeneration; snRNA‐seq; Substantia alba; Transcriptomes; Transcriptomics; Vascular dementia; white matter; White Matter - metabolism; White Matter - pathology; disease-associated endothelial cells; white matter; angiogenesis; vascular dementia; snRNA-seq
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.17315

Background Vascular dementia (VaD) is the accumulation of vascular lesions in the subcortical white matter of the brain. These lesions progress and there is no direct medical therapy. Aims To determine the specific cellular responses in VaD so as to provide molecular targets for therapeutic development. Materials and Methods Single‐nucleus transcriptome analysis was performed in human periventricular white matter (PVWM) samples of VaD and normal control (NC) subjects. Results Differential analysis shows that cell type‐specific transcriptomic changes in VaD are associated with the disruption of specific biological processes, including angiogenesis, immune activation, axonal injury and myelination. Each cell type in the neurovascular unit within white matter has a specific alteration in gene expression in VaD. In a central cell type for this disease, subcluster analysis of endothelial cells (EC) indicates that VaD contains a disease‐associated EC subcluster that expresses genes associated with programmed cell death and a response to protein folding. Two other subpopulations of EC in VaD express molecular systems associated with regenerative processes in angiogenesis, and in axonal sprouting and oligodendrocyte progenitor cell maturation. Conclusion This comprehensive molecular profiling of brain samples from patients with VaD reveals previously unknown molecular changes in cells of the neurovascular niche, and an attempt at regeneration in injured white matter.