Transcriptomic signatures of individual cell types in cerebral cavernous malformation
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Published:2024-01-09
Issue:1
Volume:22
Page:
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ISSN:1478-811X
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Container-title:Cell Communication and Signaling
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language:en
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Short-container-title:Cell Commun Signal
Author:
Li YingORCID, Girard Romuald, Srinath Abhinav, Cruz Diana Vera, Ciszewski Cezary, Chen Chang, Lightle Rhonda, Romanos Sharbel, Sone Je Yeong, Moore Thomas, DeBiasse Dorothy, Stadnik Agnieszka, Lee Justine J., Shenkar RobertORCID, Koskimäki Janne, Lopez-Ramirez Miguel A., Marchuk Douglas A., Ginsberg Mark H., Kahn Mark L., Shi Changbin, Awad Issam A.ORCID
Abstract
AbstractCerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets.
Funder
Brave for Life Foundation NINDS/NIH National Natural Science Foundation of China Key Project of Natural Science Foundation of Heilongjiang Province of China Foundation for High-Level Returned Overseas Talents of Ministry of Human Resources and Social Security of China
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology,Biochemistry
Reference87 articles.
1. Flemming KD, Graff-Radford J, Aakre J, Kantarci K, Lanzino G, Brown RD Jr, Mielke MM, Roberts RO, Kremers W, Knopman DS, et al. Population-based prevalence of cerebral cavernous malformations in older adults: Mayo Clinic study of aging. JAMA Neurol. 2017;74:801–5. 2. Akers A, Salman RA, Awad IA, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, et al. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery. 2017; 80: 665–680. 3. Al-Shahi Salman R, Hall JM, Horne MA, Moultrie F, Josephson CB, Bhattacharya JJ, Counsell CE, Murray GD, Papanastassiou V, Ritchie V, et al. Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol. 2012;11:217–24. 4. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, Maxwell SS, White P, Christianson TJ, Agid R, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15:166–73. 5. Polster SP, Stadnik A, Akers AL, Cao Y, Christoforidis GA, Fam MD, Flemming KD, Girard R, Hobson N, Koenig JI, et al. Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial. Neurosurgery. 2019;85:843–53.
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