Dataset Information

Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization.

ABSTRACT: Pigment epithelium-derived factor (PEDF) is a serine proteinase inhibitor with antiangiogenic activities. To investigate whether PEDF overexpression has an impact on ocular neovascularization in vivo, we generated PEDF transgenic (PEDF-Tg) mice that ubiquitously express human PEDF driven by the ?-actin promoter. The PEDF-Tg mice under normal conditions did not show any abnormalities in retinal histologic findings or visual function. In contrast, PEDF-Tg animals with oxygen-induced retinopathy (OIR) developed significantly less severe retinal neovascularization compared with wild-type (Wt) mice with OIR. In addition, PEDF-Tg mice with OIR had significantly lower vascular leakage in the retina but higher occludin levels than the Wt mice with OIR, suggesting a protective effect on the blood-retinal barrier. Furthermore, retinal levels of proinflammatory factors were significantly lower in PEDF-Tg mice with OIR than in the Wt mice with OIR. In the laser-induced choroidal neovascularization (CNV) model, the CNV area was significantly smaller in the PEDF-Tg mice than in the Wt mice. Also, the laser burn-induced overexpression of proangiogenic and inflammatory factors was observed in the retina and retinal pigment epithelium of Wt mice but not in PEDF-Tg mice. Taken together, these results suggest that overexpression of PEDF inhibits retinal inflammation and neovascularization in both the OIR and laser-induced CNV models. The PEDF-Tg mice provide a useful model for studying the roles of angiogenic inhibitors in neovascular disorders such as diabetic retinopathy.

SUBMITTER: Park K

PROVIDER: S-EPMC3070578 | biostudies-other | 2011 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization.

Park Kyoungmin K Jin Ji J Hu Yang Y Zhou Kevin K Ma Jian-xing JX

The American journal of pathology 20110201 2

Pigment epithelium-derived factor (PEDF) is a serine proteinase inhibitor with antiangiogenic activities. To investigate whether PEDF overexpression has an impact on ocular neovascularization in vivo, we generated PEDF transgenic (PEDF-Tg) mice that ubiquitously express human PEDF driven by the β-actin promoter. The PEDF-Tg mice under normal conditions did not show any abnormalities in retinal histologic findings or visual function. In contrast, PEDF-Tg animals with oxygen-induced retinopathy (O ...[more]

PMID: 21281801

Similar Datasets

Project description:Retinal ganglion cells (RGCs) undergo rapid cell death by apoptosis after injury but can be rescued by suppression of caspase-2 (CASP2) using an siRNA to CASP2 (siCASP2). Pigment epithelium-derived factor (PEDF), has neuroprotective and anti-angiogenic functions and protects RGC from death. The purpose of this study was to investigate if suppression of CASP2 is a possible mechanism of neuroprotection by PEDF in RGC. Adult rat retinal cells were treated in vitro with sub-optimal and optimal concentrations of siCASP2 and PEDF and levels of CASP2 mRNA and RGC survival were then quantified. Optic nerve crush (ONC) injury followed by intravitreal injections of siCASP2 or PEDF and eye drops of PEDF-34 were also used to determine CASP2 mRNA and protein reduction. Results showed that PEDF and PEDF-34 significantly suppressed CASP2 mRNA in culture, by 1.85- and 3.04-fold, respectively, and increased RGC survival by 63.2?±?3.8% and 81.9?±?6.6%, respectively compared to cells grown in Neurobasal-A alone. RGC survival was significantly reduced in glial proliferation inhibited and purified RGC cultures suggesting that some of the effects of PEDF were glia-mediated. In addition, intravitreal injection of PEDF and eye drops of PEDF-34 after ONC also suppressed CASP2 mRNA levels by 1.82- and 3.89-fold and cleaved caspase-2 (C-CASP2) protein levels by 4.98- and 8.93-fold compared to ONC?+?PBS vehicle groups, respectively, without affecting other executioner caspases. Treatment of retinal cultures with PEDF and PEDF-34 promoted the secretion of neurotrophic factors (NTF) into the culture media, of which brain-derived neurotrophic factor (BDNF) caused the greatest reduction in CASP2 mRNA and C-CASP2 protein. The neuroprotective effects of PEDF were blocked by a polyclonal antibody and PEDF suppressed key elements in the apoptotic pathway. In conclusion, this study shows that some of the RGC neuroprotective effects of PEDF is regulated through suppression of CASP2 and downstream apoptotic signalling molecules.

Project description:The therapeutic potential of pluripotent stem cells is great as they promise to usher in a new era of medicine where cells or organs may be prescribed to replace dysfunctional tissue. At the forefront are efforts in the eye to develop this technology as it lends itself to in vivo monitoring and sophisticated non-invasive imaging modalities. In the retina, retinal pigment epithelium (RPE) is the most promising replacement cell as it has a single layer, is relatively simple to transplant, and is associated with several eye diseases. However, after transplantation, the cells may transform and cause complications. This transformation may be partially due to incomplete maturation. With the goal of learning how to mature RPE, we compared induced pluripotent stem cell-derived RPE (iPSC-RPE) cells with adult human primary RPE (ahRPE) cells and the immortalized human ARPE-19 line. We cultured ARPE-19, iPSC-RPE, and ahRPE cells for one month, and evaluated morphology, RPE marker staining, and transepithelial electrical resistance (TEER) as quality control indicators. We then isolated RNA for bulk RNA-sequencing and DNA for genotyping. We genotyped ahRPE lines for the top age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR) risk allele polymorphisms. Transcriptome data verified that both adult and iPSC-RPE exhibit similar RPE gene expression signatures, significantly higher than ARPE-19. In addition, in iPSC-RPE, genes relating to stem cell maintenance, retina development, and muscle contraction were significantly upregulated compared to ahRPE. We compared ahRPE to iPSC-RPE in a model of epithelial-mesenchymal transition (EMT) and observed an increased sensitivity of iPSC-RPE to producing contractile aggregates in vitro which resembles incident reports upon transplantation. P38 inhibition was capable of inhibiting iPSC-RPE-derived aggregates. In summary, we find that the transcriptomic signature of iPSC-RPE conveys an immature RPE state which may be ameliorated by targeting "immature" gene regulatory networks.

Dataset Information

Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization.

Publications

Overexpression of pigment epithelium-derived factor inhibits retinal inflammation and neovascularization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets