In:
Science, American Association for the Advancement of Science (AAAS), Vol. 375, No. 6584 ( 2022-03-04)
Kurzfassung:
The cerebrovasculature delivers nourishment and regulates blood-brain molecular exchanges that are necessary for neurologic function. Coordinated communications between multiple cell types—including endothelium, pericytes, smooth muscle cells, and perivascular fibroblasts—provides the basis for the functional specialization of arteries, capillaries, and veins. Cellular dysfunction results in cerebrovascular diseases, a leading cause of death and disability. However, we currently lack a comprehensive atlas of cerebrovascular cells in the human brain. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. RATIONALE To provide a human cerebrovascular cell atlas, we used single-cell mRNA sequencing (scRNA-seq), using dissociated vascular cells isolated from the adult human brain and arteriovenous malformations (AVMs), a cerebrovascular disease of arteriovenous patterning in which patients are prone to bleeding and stroke. Using marker genes identified from single-cell transcriptomes, we characterized spatial distributions of cerebrovascular cell states with multiplexed fluorescent in situ hybridization and immunostaining. Joint comparative analyses between scRNA-seq datasets systematically profiled patterns of aberrant gene expression in AVMs. To investigate potential relevance of these findings, we performed in silico analyses to catalog dysregulated cell-to-cell interactions and to resolve cell states enriched in advanced stages of AVMs that bled. Predictions were validated with immunostaining and functional assays in cell culture. RESULTS By performing scRNA-seq on 181,388 individual cells, we identified more than 40 transcriptomically defined cell states of vascular, immune, and neighboring glial or neuronal cells from the human adult cerebrovasculature and AVMs. Iterative analyses of single-cell gene expression profiles revealed endothelial molecular signatures underlying arteriovenous phenotypic changes called zonations. Our study uncovered an expanded diversity of perivascular cells in human but not mouse brain, including a molecular marker of pericytes, transcriptional variation within smooth muscle cells and perivascular fibroblasts, and the presence of smooth muscle–like cells known as fibromyocytes. In AVMs, our data suggested a loss of normal zonation among endothelial cells. Moreover, we observed the emergence of a distinct transcriptomic state that corresponded to the nidus, which was characterized by heightened angiogenic potential and immune cell cross-talk. In addition, we characterized the cellular ontology of the cerebrovascularly derived immune cell response and identified infiltration of distinct immune cell states, such as GPNMB + monocytes, which contribute to depletion of stabilizing smooth muscle cells in AVMs that bled. CONCLUSION Our single-cell atlas highlights the transcriptomic heterogeneity underlying cell function and interaction in the human cerebrovasculature and defines molecular and cellular perturbations in AVMs, a leading cause of stroke in young people. The identified interplay between vascular and immune cells may aid the development of therapeutics that target angiogenic and inflammatory programs in vascular malformations. More broadly, this cell atlas should inform future studies in other human diseases to accelerate mechanistic understanding and therapeutic targeting of the human cerebrovasculature and its diseases. The adult human cerebrovascular cell atlas. We used scRNA-seq to assemble a cerebrovascular cell atlas from the adult human brain and AVMs. Findings were then experimentally validated. Comparative analyses revealed endothelial molecular transformations and heightened immune cell response in AVMs. Using this cell atlas, we identified immune cell states implicated in AVM rupture and brain hemorrhage. IMAGE: NOEL SIRIVANSANTI AND KEN PROBST
Materialart:
Online-Ressource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abi7377
Sprache:
Englisch
Verlag:
American Association for the Advancement of Science (AAAS)
Publikationsdatum:
2022
ZDB Id:
128410-1
ZDB Id:
2066996-3
ZDB Id:
2060783-0
SSG:
11
