A single-cell atlas of the normal and malformed human brain vasculature

Winkler, Ethan A.; Kim, Chang N.; Ross, Jayden; Garcia, Joseph H.; Gil, Eugene; Oh, Irene; Chen, Lindsay Q; Wu, David; Catapano, Joshua S; Raygor, Kunal P.; Narsinh, Kazim; Kim, Helen; Weinsheimer, Shantel; Cooke, Daniel L; Walcott, Brian P.; Lawton, Michael T.; Gupta, Nalin; Zloković, Berislav V.; Chang, Edward F.; Abla, Adib A.; Lim, Daniel A.; Nowakowski, Tomasz J.

doi:10.1126/science.abi7377

Cited by 189 publications

(197 citation statements)

References 90 publications

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“…To further delineate the cellular origin and functional consequences of FGD6 expression in the cerebrovascular system, we utilize scRNA-seq data derived from normal adult human brain endothelial and perivascular cells as previously described. 19 We find that FGD6 is highly expressed in 1 of 3 arterial lineages, venules, and veins but FGD6 expression is largely undetectable across 12 perivascular cell lineages (Figure 5A-B). These findings will facilitate additional mechanistic studies aimed at understanding the molecular basis of FGD6 dysfunction underlying rIA.…”

Section: Resultsmentioning

confidence: 83%

“…Gene-burden analysis provides convergent evidence supporting the FGD6 gene in rIA risk. Functional characterization indicates that genetic variation in FGD6 loci contributes to rIA risk by decreasing FGD6 gene expression in arterial tissue, Utilization of single-cell RNA sequencing analysis of human brain endothelial and perivascular cells 19 characterizes FGD6 expression across rIA-relevant neurovascular cell types where alterations in FGD6 expression may alter cell identity and function. These data will inform detailed mechanistic analysis of FGD6 in rIA biology and perhaps even treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Finally, we utilized single-cell RNA sequencing analysis of adult human brain endothelial and perivascular cells obtained from normal brain cortex biopsies obtained as previously described. 19 Statistics Experiment-specific statistical methods are discussed above. Thresholds, controls, and statistical tests are indicated in each Figure legend.…”

Section: Functional Genomics Analysismentioning

confidence: 99%

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Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Hale

Jones

2022

Preprint

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Importance: The genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the ~50% mortality rate of rIA, approaches to identify patients at high-risk will inform screening, diagnostic, and preventative measures. Objective: To identify and characterize the genetic basis of rIA. Design: We perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. Setting: We perform a meta-analysis across 24 published GWAS of rIA. Participants: Our cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). Main Outcome and Measure: Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. Results: We identify 5 independent genetic loci reaching genome-wide significance (p<5.0x10-8) for rIA including rs12310399 (FGD6, OR=1.16), which to our knowledge, has not been implicated in prior GWAS of (r)IA. We then quantified gene-level mutation-burden across ~20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Expression quantitative trait loci (eQTL) mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery identified high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. Patients with a Mendelian disease caused by FGD6 mutations (Aarskog-Scott syndrome) have been diagnosed with rIA, among other features, providing direct causal evidence for FGD6 in rIA pathogenesis. Conclusions and Relevance: We identify and characterize a previously unknown risk loci for rIA containing FGD6. Variable expressivity of FDG6 causes a range of clinical features from Mendelian disease to sporadic rIA. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Functional Genomics Analysismentioning

confidence: 99%

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Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Hale

Jones

2022

Preprint

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“…Indeed, members of our group have previously reported endovascular biopsy and single-cell RNAseq results from animal and human samples. (26)(27)(28)30,(32)(33)(34) However, these techniques lack spatial information, so it cannot be known from where certain gene expression findings originate.…”

Section: Introductionmentioning

confidence: 99%

Spatially Resolved Transcriptomics for Evaluation of Intracranial Vessels in a Rabbit Model: Proof of Concept

Zabriskie

Cooke

Wang

et al. 2022

Preprint

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Background Better understanding is needed of the vessel biology specific to vessels and the pathologies they can harbor to develop better treatments. Rabbit models can be effective for studying intracranial vessels, filling gaps resulting from difficulties acquiring human tissue. Spatially-resolved transcriptomics (SRT) in particular hold promise for studying such models as they build on RNA sequencing methods, augmenting such data with histopathology. Methods Rabbit brains with intact arteries were flash frozen, cryosectioned, and stained with H&E to confirm adequate inclusion of intracranial vessels before proceeding with tissue optimization and gene expression analysis using the Visium SRT platform. SRT results were analyzed with k-means clustering analysis, and differential gene expression was examined, comparing arteries to veins. Results Cryosections were successfully mounted on Visium proprietary slides. Quality control thresholds were met. Optimum permeabilization was determined to be 24 minutes for the tissue optimization step. In analysis of SRT data, k-means clustering distinguished vascular tissue from parenchyma. When comparing gene expression traits, the most differentially expressed genes were those found in smooth muscle cells. These genes were more commonly expressed in arteries compared to veins. Conclusions Intracranial vessels from model rabbits can be processed and analyzed with the Visium SRT platform. Face validity is found in the ability of SRT data to distinguish vessels from parenchymal tissue and differential expression analysis accurately distinguishing arteries from veins. SRT should be considered for future animal model investigations into cerebrovascular diseases.

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Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

Ji,

Han,

Danyang Jie

et al. 2024

Ann Clin Transl Neurol

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ObjectiveAbundant neutrophils have been identified in both ruptured and unruptured intracranial aneurysm (IA) domes, with their function and clinical implication being poorly characterized.Materials and MethodsWe employed single‐cell RNA sequencing (scRNA‐Seq) datasets of both human and murine model, and external bulk mRNA sequencing datasets to thoroughly explore the features and functional heterogeneous of neutrophils infiltrating the IA dome.ResultsWe found that both unruptured and ruptured IA dome contain a substantial population of neutrophils, characterized by FCGR3B, G0S2, CSF3R, and CXCR2. These cells exhibited heterogeneity in terms of function and differentiation. Despite similar transcriptional activation, neutrophils in IA dome expressed a repertoire of gene programs that mimicked transcriptomic alterations observed from bone marrow to peripheral blood, showing self‐similarity. In addition, the recruitment of neutrophils in unruptured IA was primarily mediated by monocytes/macrophages, and once ruptured, both neutrophils, and a specific subset of inflammatory smooth muscle cells (SMCs) were involved in the process. The receiver operator characteristic curve (ROC) analysis indicated that distinct neutrophil subclusters were associated with IA formation and rupture, respectively. By reviewing current studies, we found that neutrophils play a detrimental role to IA wall integrity through secreting specific ligands, ferroptosis driven by ALOX5AP and PTGS2, and the formation of neutrophil extracellular traps (NETs) mediated by PADI4.InterpretationThis study delineated the biology and potential clinical implications of neutrophils in IA dome and provided a reliable basis for future researches.

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A single-cell atlas of the normal and malformed human brain vasculature

Cited by 189 publications

References 90 publications

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Spatially Resolved Transcriptomics for Evaluation of Intracranial Vessels in a Rabbit Model: Proof of Concept

Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

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