Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Impaired RPE Mitochondrial Energetics Leads Subretinal Fibrosis in Neovascular Age-related Macular Degeneration

ABSTRACT: Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr-/- mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGFβ2 induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGFβ receptor I/II complex by interacting with unglycosylated TGFβ receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFβ2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE221952 | GEO | 2024/08/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

Project description:Macular subretinal fibrosis is the end-stage complication of neovascular age-related macular degeneration (nAMD). RPE/Choroid from control and subretinal fibrosis mice were collected and processed for RNA sequencing (RNA-seq) analysis to investigate the molecular mechanism of subretinal fibrosis.

2022-04-13 | GSE189555 | GEO

Single -cell transcriptomic profiling of stem cell derived retinal pigment epithelial cell monolayers after subretinal transplantation

Project description:Transplantation of stem cell derived retinal pigment epithelial (RPE) cells can potentially restore vision in patients with age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limited efficacy. Currently, there is limited understanding of how the recipient retina regulates the survival, maturation and fate specification of transplanted RPE cells. To address this, we transplanted stem cell derived RPE into the subretinal space of immunocompetent rabbits for one month and conducted single-cell RNA sequencing analyses on the explanted RPE monolayers, compared to their age-matched in vitro counterparts. We observed an unequivocal retention of RPE identity, and a trajectory inferred survival of all in vitro RPE populations after transplantation. Furthermore, there was a unidirectional maturation trajectory towards the native adult human RPE state in all transplanted RPE cells, regardless of stem cell resource. Using adult human RPE cells as a reference, we reconstructed the gene regulatory networks in our transplanted stem cell derived RPE, and identified tripartite transcription factors (MAFF, JUND and FOS), known to modulate a broad array of RPE functions in vivo. This includes regulation of canonical RPE signature genes known to support host photoreceptors, and pro-survival genes required for adaptation to the host subretinal microenvironment. These findings shed insights into the transcriptional landscape of RPE cells after subretinal transplantation, with important implications for cell-based therapy for AMD.

2023-05-22 | GSE212896 | GEO

Interleukin-17-Mediated Protective Cytokine Signaling Against Degeneration of the Retinal Pigment Epithelium

Project description:Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal gd T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to delve deeper into the mechanisms involved. We found that gd T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor on the RPE, subsequently triggering the production of interleukin-6 (IL-6). This cascade of cytokines initiated a metabolic reprogramming of subretinal microglia, enhancing their capacity for lipid metabolism. RPE-specific knockout of IL-17 receptor A led to the dysfunction of subretinal microglia and RPE pathology. Collectively, our findings suggest that responding to RPE injury, the choroidal gd T cells can initiate a protective signaling cascade that ensures the proper functioning of subretinal microglia.

2023-11-29 | GSE244661 | GEO

Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

Project description:Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

| PRJNA783568 | ENA

TGF-Beta 3 heterozygous mice

Project description:Transforming growth factor β (TGFβ) family comprises the main player in the development of fibrosis including three isoforms: TGFβ1, TGFβ2 and TGFβ3. TGFβ3 may play an antifibrotic role at the renal level, counteracting the role of TGFβ1, using a mouse model heterozygous for the TGFβ3 gene (TGFβ3+/-). Partial deletion of TGFβ3 causes in the mice albuminuria, loss of glomerular filtration rate, accelerated fibrosis, epithelial-to-mesenchymal transition and increment of glomerular basement membrane thickening.

2019-12-19 | ST001303 | MetabolomicsWorkbench

Mouse RPE-Choroids mRNA profiles of 4-week subretinal injection of AAV-GFP/PDGF-D

Project description:Mouse RPE-Choroids mRNA profiles of 4-week subretinal injection of AAV-GFP/PDGF-D

| PRJNA692714 | ENA

Effect of cAMP and seeding density on RPE redifferentiation

Project description:Retinal pigment epithelium (RPE) cell integrity is critical to the maintenance of retinal function. Many retinopathies such as age-related macular degeneration (AMD) are caused by the degeneration or malfunction of the RPE cell layer. Replacement of diseased RPE with healthy, stem cell derived RPE is a potential therapeutic strategy for treating AMD. Human embryonic stem cells (hESC) differentiated into RPE progeny have potential to provide an unlimited supply of cells for transplantation but challenges around scalability and efficiency of the differentiation process still remain. Using hESC-derived RPE as a cellular model, we sought to understand mechanisms that could be modulated to increase RPE yield following differentiation. Our data show that activation of the cAMP pathway increases proliferation of dissociated RPE in culture, in part through inhibition of TGFβ signalling. This in turn results in enhanced uptake of epithelial identity. In line with these findings, targeted manipulation of the TGFβ pathway with small molecules produces an increase in efficiency of RPE re-epithelialization. Taken together, these data highlight mechanisms that promote epithelial fate acquisition in stem cell derived RPE. Modulation of these pathways has potential to favorably impact upon scalability and clinical translation of hESC-derived RPE as a cell therapy. A sample of Gene Pool™ cDNA, from human fetal normal brain tissue (Invitrogen D8830-01) is included for reference.

2015-09-14 | E-MTAB-3878 | biostudies-arrayexpress

Sex differences in the expression and function of hepatic very low-density lipoprotein receptor during protein deficiency in mice

Project description:Very low-density lipoprotein (VLDL) receptor (VLDLR), a member of the low-density lipoprotein receptor family, is responsible for VLDL uptake in peripheral tissues. We reported that significant increase in hepatic VLDLR levels following protein restriction in male mice does not contribute to hepatic fat accumulation, indicating that VLDLR may have hitherto unknown functions. Here, we used RNA-sequencing analysis of liver samples to analysis the effects of protein restriction on hepatic VLDLR in male and female mice.

2024-02-27 | GSE259313 | GEO

Effects of selective elimination of senescent cells on RPE/choroid complex in mice with subretinal drusenoid deposits

Project description:The target deletion of ATP binding cassette subfamily member 1 (ABCA1) and G1 (ABCG1) in myeloid cells leads to subretinal drusenoid deposits in mice (Abca1/g1 -m/-m). We here report the selective elimination of p16-positive cells results in the significant eduction in myeloid markers, pro-inflammatory cytokines and prostaglandin biosynthetic enzymes.

2024-04-17 | GSE234641 | GEO

Myocardin-like Protein (MKL)-2 Regulates TGF-β Signaling in Embryonic Stem Cells and the Developing Vasculature

Project description:Signal transduction from the extracellular matrix to the arterial wall plays a critical role during development of the vasculature. We now report the discovery of a Myocardin-like Protein (MKL)2/TGF-β signaling pathway that is required for maturation and stabilization of the vasculature. Mkl2-/- null embryos exhibit profound derangements in the tunica media leading to aneurismal dilation, dissection and hemorrhage. TGFβ expression, signaling and TGF-β-regulated genes are down-regulated in Mkl2-/- ES cells and in the vasculature of Mkl2-/- embryos. Transcription of Tgfβ2 is activated via binding of a MKL 2/SRF complex to a conserved CArG element in the Tgfβ2 promoter. In this data set we include expression data from wild type and Mkl2-/- ES cells A total of 5 samples with mRNA of sufficient quality were analyzed. Samples consisted of mRNA from independent cell culture of 2 wild-type and 3 Mkl2-/- undifferentiated Embryonic Stem Cells

2012-05-31 | E-GEOD-38316 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data