Single-cell transcriptome of wet AMD patient-derived endothelial cells in angiogenic sprouting
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PROVIDER: PRJNA883213 | ENA |
REPOSITORIES: ENA
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Project description:Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. ‘Wet’ AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our ‘activated’ BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome (https://christinecheunglab.shinyapps.io/human_wet_AMD_sprouting/) has been created to facilitate further discovery research.
2022-11-02 | GSE213933 | GEO
Project description:Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-VEGF biologics, there is a need for the novel development of less invasive treatments. Here, we developed a novel inhibitor of microtubule-associated End Binding 3 protein (EB3), herein termed EBIN, which blocked pathological Ca2+ signaling in activated endothelial cells and suppressed leakage of choroidal neovessels. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of AMD prevented neovascular leakage and neovascularization as effectively as intravitreal injection of anti-VEGF therapy. EBIN activated Meis2-Pax6 regenerative pathways in metabolic-active endothelial cells comprising neovessels and promoted tissue regeneration. Furthermore, single nuclei assay for transposase-accessible chromatin sequencing (sn-ATAC-seq) analysis demonstrated that in metabolic-active endothelial cells, the RPE, and photoreceptors, EBIN induced global increases in chromatin accessibility, the biological process progressively inhibited in AMD patients. These results suggest the unique therapeutic mode of action of this novel drug candidate, which can potentially promote regeneration of eye tissue by reversing the degenerative processes underlying both the neovascular and atrophic forms of AMD.
2023-08-30 | GSE228273 | GEO
Project description:Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-VEGF biologics, there is a need for the novel development of less invasive treatments. Here, we developed a novel inhibitor of microtubule-associated End Binding 3 protein (EB3), herein termed EBIN, which blocked pathological Ca2+ signaling in activated endothelial cells and suppressed leakage of choroidal neovessels. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of AMD prevented neovascular leakage and neovascularization as effectively as intravitreal injection of anti-VEGF therapy. EBIN activated Meis2-Pax6 regenerative pathways in metabolic-active endothelial cells comprising neovessels and promoted tissue regeneration. Furthermore, single nuclei assay for transposase-accessible chromatin sequencing (sn-ATAC-seq) analysis demonstrated that in metabolic-active endothelial cells, the RPE, and photoreceptors, EBIN induced global increases in chromatin accessibility, the biological process progressively inhibited in AMD patients. These results suggest the unique therapeutic mode of action of this novel drug candidate, which can potentially promote regeneration of eye tissue by reversing the degenerative processes underlying both the neovascular and atrophic forms of AMD.
2023-08-30 | GSE228270 | GEO
Project description:Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-VEGF biologics, there is a need for the novel development of less invasive treatments. Here, we developed a novel inhibitor of microtubule-associated End Binding 3 protein (EB3), herein termed EBIN, which blocked pathological Ca2+ signaling in activated endothelial cells and suppressed leakage of choroidal neovessels. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of AMD prevented neovascular leakage and neovascularization as effectively as intravitreal injection of anti-VEGF therapy. EBIN activated Meis2-Pax6 regenerative pathways in metabolic-active endothelial cells comprising neovessels and promoted tissue regeneration. Furthermore, single nuclei assay for transposase-accessible chromatin sequencing (sn-ATAC-seq) analysis demonstrated that in metabolic-active endothelial cells, the RPE, and photoreceptors, EBIN induced global increases in chromatin accessibility, the biological process progressively inhibited in AMD patients. These results suggest the unique therapeutic mode of action of this novel drug candidate, which can potentially promote regeneration of eye tissue by reversing the degenerative processes underlying both the neovascular and atrophic forms of AMD.
2023-08-30 | GSE228269 | GEO
Project description:To identify previously unknown determinants of endothelial cell sprouting, we defined and exploited a pharmacological strategy for the manipulation of angiogenic cell behavior in vivo. Whereas high vascular endothelial growth factor receptor (Vegfr) signaling is known to promote tip cell (TC) specification, activation of the Notch receptor via its ligand Delta-like 4 (Dll4) represses the TC phenotype to promote stalk cell (SC) fate. Conversely, suppression of Notch activity upon antagonistic interaction with its ligand Jagged1 pro- motes TC formation. Hence, specification of TCs involves tight spatiotemporal control of Vegfr/Notch signaling. Consequently, we hypothesized that the pharmacological manipulation of Vegfr/Notch signaling selectively during zebrafish intersegmental vessel (ISV) angiogenesis would enable the precise control of angiogenic EC behavior and sprouting- associated gene expression in vivo. For more information, see Herbert et al., 2012, PMID 22921365.
2019-05-09 | GSE130889 | GEO
Project description:Several environmental pollutants have been reported to exhibit either pro-angiogenic or anti-angiogenic effects, which may contribute to related vascular diseases. However, the specific mechanism by which pollutants induce sprouting angiogenesis is unclear, and there are few studies on the association between the site of hyperangiogenesis and vascular diseases. In this study, zebrafish were exposed to bisphenol S (BPS, 1~100 µg/L) and tetrabromobisphenol S (TBBPS, 0.1 and 10 µg/L) from the embryonic to the larval stage to investigate how pollutants interfere with the function of ectopic sprouting vessels. Results showed that BPS and TBBPS promoted ectopic sprouting angiogenesis in different types of vascular plexus at different developmental time points but inhibited vascular endothelial-cadherin (VE-cadherin) expression. The proteomic analyses on eGFP-positive endothelial cells isolated from Tg(flk1: eGFP) zebrafish indicated that both BPS and TBBPS induced ectopic angiogenesis through inhibiting VE-cadherin-mediated adherens junction and activating the downstream pro-angiogenic signaling. In ectopic sprouting vessels induced by BPS and TBBPS, an increased endothelial permeability resulted in white blood cells recruitment and erythrocyte retention. Human oxidized lipids were also prone to deposit in these ectopic vessels following BPS and TBBPS exposure. This suggests that ectopic angiogenesis is a cause of vascular dysfunction and related diseases.
2024-11-12 | PXD057764 |
Project description:Inhibition of EB3 activates the Meis2-Pax6 regenerative program in wet AMD
| PRJNA949182 | ENA
Project description:Endothelial TIE1 restricts angiogenic sprouting to coordinate vein assembly in synergy with its homologue TIE2
| PRJNA952988 | ENA
Project description:Identifying new markers of angiogenic sprouting using transcriptomics: New role for RND3
| PRJNA1071678 | ENA
Project description:Class IIa histone deacetylases (HDACs) are signal-responsive regulators of gene expression involved in vascular homeostasis. To investigate the differential role of class IIa HDACs for the regulation of angiogenesis, we used siRNA to specifically suppress the individual HDAC isoenzymes. Among the HDAC isoforms tested, silencing of HDAC5 exhibited a unique pro-angiogenic effect evidenced by increased endothelial cell migration, sprouting and tube formation. Consistently, overexpression of HDAC5 decreased sprout formation, indicating that HDAC5 is a negative regulator of angiogenesis. The anti-angiogenic activity of HDAC5 was independent of MEF2 binding and its deacetylase activity, but required a nuclear localization indicating that HDAC5 might affect the transcriptional regulation of gene expression. To identify putative HDAC5 targets, we performed microarray expression analysis. Silencing of HDAC5 increased the expression of fibroblast growth factor 2 (FGF2) and angiogenic guidance factors including Slit2. Antagonization of FGF2 or Slit2 reduced sprout induction in response to HDAC5 siRNA. ChIP assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. In summary, HDAC5 represses angiogenic genes, like FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. The de-repression of angiogenic genes by HDAC5 inactivation may provide a useful therapeutic target for induction of angiogenesis.
2009-04-02 | GSE15499 | GEO