Transcriptional Comparison of Human and Murine Retinal Neovascularization
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ABSTRACT:
PROVIDER: PRJNA981457 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24874948.fastq.gz | Fastqsanger.gz | |||
| SRR24874949.fastq.gz | Fastqsanger.gz | |||
| SRR24874950.fastq.gz | Fastqsanger.gz | |||
| SRR24874951.fastq.gz | Fastqsanger.gz | |||
| SRR24874952.fastq.gz | Fastqsanger.gz |
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Project description:Background: Retinal neovascularization (RNV) as a result of retinal ischemia, such as in proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP), can lead to vitreous hemorrhage, tractional retinal detachment, and irreversible loss of vision if left untreated. Although panretinal laser photocoagulation and anti-vascular endothelial growth factor (VEGF) injections are efficient treatment modalities, a significant number of patients do not respond to either treatment. This clinical finding suggests that other, previously unrecognized mediators and signaling pathways may contribute to RNV development and could represent valuable targets for future treatments. Methods: In search of phylogenetically conserved angiogenic mediators, we examined the transcriptional profile of murine RNV from C57BL/6J mice (n=14) in the oxygen-induced retinopathy (OIR) model as well as human RNV membranes from PDR patients (n=7), who had undergone vitrectomy and compared them with corresponding control tissues (n=13, 10 respectively). Genes that were differentially expressed (DEGs) between RNV and control samples were identified for human and murine samples and their associated gene ontology (GO) clusters analyzed. Lastly, human and murine DEGs were compared to identify phylogenetically conserved factors. Findings: Transcriptional profiles of murine RNV showed that DEGs linked to the activation of the innate immune system (Msn, Cd34), extracellular matrix organisation (Col4a1, Gfap), and regulation of angiogenesis (Col4a2, Fgf2) were significantly upregulated both at the ischemic, preproliferative stage of the disease (OIR p14) as well as at the proliferative stage (OIR p17). While similar GO terms were upregulated in human RNV, only a small overlap in DEGs between both species was detected. Phylogenetically conserved mediators upregulated in both murine and human RNV included ANGPT2, S100A8, MCAM, EDNRA, MRC1, and CCR7. Interpretation: This study identifies phylogenetically conserved inflammatory and pro-angiogenic mediators that are significantly upregulated in both murine and human RNV. Among them, MCAM, ENDRA and MRC1 emerged as the most upregulated, phylogenetically conserved DEGs not yet implicated in human RNV, thus representing potential new treatment targets for ischemic retinal diseases.
2024-01-03 | GSE234447 | GEO
Project description:In order to find out the vital genes during retinal neovascularization (RNV), we set up OIR (oxygen-induced retinopathy; induced with 75%±2% oxygen) and wild-type C57BL/6J murine models. We observed the retinal vascular growth process daily both in OIR and wild-type mice through retinal flat-mount, and isolated total retinal RNA at different time points (P8, P9, P12, P13, P30) both in OIR and wild-type mice for gene expression analysis. At least three different retinae were accessed at each time point for observing the retinal vascular growth process. Ten neural retinae from five mice were harvested and pooled into one sample for gene expression analysis. Three biological replicates were used for each time point. Dye-swaps were performed.
2012-12-05 | E-GEOD-38762 | biostudies-arrayexpress
Project description:In order to find out the vital genes during retinal neovascularization (RNV), we set up OIR (oxygen-induced retinopathy; induced with 75%±2% oxygen) and wild-type C57BL/6J murine models. We observed the retinal vascular growth process daily both in OIR and wild-type mice through retinal flat-mount, and isolated total retinal RNA at different time points (P8, P9, P12, P13, P30) both in OIR and wild-type mice for gene expression analysis.
2012-12-05 | GSE38762 | GEO
Project description:PurposeRetinal neovascularization (RNV) is the leading cause of vision loss in diseases like proliferative diabetic retinopathy (PDR). A significant failure rate of current treatments indicates the need for novel treatment targets. Animal models are crucial in this process, but current diabetic retinopathy models do not develop RNV. Although the nondiabetic oxygen-induced retinopathy (OIR) mouse model is used to study RNV development, it is largely unknown how closely it resembles human PDR.MethodsWe therefore performed RNA sequencing on murine (C57BL/6J) OIR retinas (n = 14) and human PDR RNV membranes (n = 7) extracted during vitrectomy, each with reference to control tissue (n=13/10). Differentially expressed genes (DEG) and associated biological processes were analyzed and compared between human and murine RNV to assess molecular overlap and identify phylogenetically conserved factors.ResultsIn total, 213 murine- and 1223 human-specific factors were upregulated with a small overlap of 94 DEG (7% of human DEG), although similar biological processes such as angiogenesis, regulation of immune response, and extracellular matrix organization were activated in both species. Phylogenetically conserved mediators included ANGPT2, S100A8, MCAM, EDNRA, and CCR7.ConclusionsEven though few individual genes were upregulated simultaneously in both species, similar biological processes appeared to be activated. These findings demonstrate the potential and limitations of the OIR model to study human PDR and identify phylogenetically conserved potential treatment targets for PDR.
| S-EPMC10756240 | biostudies-literature
Project description:Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. We report that clock genes are expressed in the embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.
2022-07-01 | GSE207271 | GEO
Project description:Pathological retinal neovascularization is a common mechanism for leading causes of vision loss including retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism controlled by the ER-resident proteins ATF6, IRE1, and PERK. In response to endoplasmic reticulum stress, UPR activates downstream transcriptional and translational programs that upregulate many proteins, including key angiogenesis factors like VEGF and HIF1a. This suggests an important role for UPR in developmental and pathologic retinal angiogenesis, but it is unclear which UPR regulatory genes are most important in these processes. Here, we focused on the role of Activating Transcription Factor 6 (ATF6) in pathologic and developmental retinal angiogenesis. We induced pathologic retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model of ROP and examined functional, histologic, and molecular consequences in the retina. we found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR and angiogenesis transcriptional programs in Atf6-/- mice after OIR. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppression of UPR and angiogenesis gene expression. Last, we examined very young Atf6-/- mice when the inner retinal vasculature is developing and found a significant defect in pruning and blood vessel extension to the periphery at P7, but this delay was transient and Atf6-/- blood vessels fully recovered at older ages of development. Together, our results demonstrate ATF6’s critical role in developmental and pathological angiogenesis and highlight its potential as a therapeutic target to mitigate pathological retinal neovascularization.
2025-08-14 | GSE292097 | GEO
Project description:Exosomes serve as signaling messengers that facilitate intercellular communication through delivering molecular cargo. Here, we observed elevated levels of exosomal periostin (POSTN) in blood plasma of patients with proliferative diabetic retinopathy (PDR). Monocytes-derived exosomal POSTN was increased under high glucose condition, and deletion of Postn in myeloid cells reduced retinal neovascularization. Monocytes isolated from the blood of PDR patients exhibited heightened glycolytic activity and elevated histone lactylation levels, particularly H4K8 lactylation (H4K8la). Knockout of Hexokinase 2 (Hk2) in myeloid cells led to reduced H4K8la and POSTN levels and inhibited retinal neovascularization. Exogenous exosomal POSTN partially reversed the angiogenic defects caused by Postn or Hk2 deletion in myeloid cells. Mechanistically, exosomal POSTN stabilized hypoxia-inducible factor 1-alpha (HIF1-α) and upregulated the expression of angiogenic genes. Notably, treatment with metformin reduced retinal neovascularization by decreasing monocytes glycolysis and lowering exosomal POSTN levels. In summary, these findings underscore the critical role of circulating exosomal POSTN in retinal neovascularization and highlight its potential as a therapeutic target for angiogenic retinopathies.
2025-01-20 | PXD059956 |
Project description:Secreted phosphoprotein 1 expression in retinal mononuclear phagocytes links murine to human choroidal neovascularization
| PRJNA671602 | ENA
Project description:Neovascular age-related macular degeneration represents the most common cause of blindness in the western world. Alterations of the outer Blood-retina barrier integrity and a localized inflammatory microenvironment lead to sprouting of choroidal neovascularization in intimate contact with surrounding myeloid cells and ultimately lead to visual impairment. The discovery of novel targets interfering with angiogenesis and inflammation is vital for the future treatments in AMD patients. To identify novel potential targets in the local phagocytes of the retina, microglia, we performed a comprehensive RNA-seq analysis in the mouse model of laser-induced choroidal neovascularization (mCNV). Here, we identified the angiogenic factor Osteopontin (Opn), also known as "secreted phosphoprotein 1” (Spp1), to be one of the most highly expressed genes in retinal microglia in the course of CNV formation. We could confirm the presence of SPP1 at the lesion site in recruited retinal microglia of Cx3cr1CreER:Rosa26-Tomato reporter mice using immunohistochemistry and in whole retinal tissue lysates by ELISA compared to controls highlighting a massive local production of SPP1. Inhibition of SPP1 by intravitreal injection of anti-SPP1 antibody significantly increased the lesion size compared to IgG-treated control eyes. In line with the results in rodents, we found an increased SPP1 mRNA expression in surgically extracted human choroidal neovascular (hCNV) membranes by the quantitative RNA-seq approach of massive analysis of cDNA ends (MACE) and found numerous IBA1+SPP1+ myeloid cells in human CNV membranes. Taken together, these results highlight the importance of SPP1 in the formation of CNV and potentially offer new opportunities for therapeutic intervention by inhibiting the SPP1 pathway.
2021-02-16 | GSE160011 | GEO
Project description:Morphological changes in the ageing eye impede oxygen delivery from the choroid to the outer retina causing tissue hypoxia, which activates a molecular response that adapts the transcriptomic fingerprint of the retina and retinal pigment epithelium (RPE). This response, orchestrated by hypoxia-inducible transcription factors (HIFs), leads to the production of pro-angiogenic factors and plays a critical role in the pathogenesis of age-related macular degeneration (AMD). To evaluate the specific contribution of HIF1 to this response we expressed a constitutively active form of HIF1A in rod photoreceptors of the adult mouse retina. This elicited a transcriptional response characterized by the upregulation of genes involved in cell death, inflammation and angiogenesis, all of which play an important role in AMD. The HIF1-mediated response in rods caused severe retinal degeneration, disruption of the RPE and retinal neovascularization. Pathological vessels originated from the deep vascular plexus and penetrated the RPE resembling type 3 macular neovascularization found in over 20% of neovascular AMD patients. Our study provides further evidence for the involvement of tissue hypoxia in the pathogenesis of AMD and highlights the potential of HIF1A as a potential therapeutic target.
2025-09-08 | GSE296005 | GEO