A Mouse Model of Proliferative Vitreoretinopathy Induced by Intravitreal Injection of Gas and RPE Cells

Abstract

Develop a reproducible proliferative vitreoretinopathy (PVR) mouse model that mimics human PVR pathology. Methods: Mice received intravitreal injections of SF 6 gas, followed by retinal pigment epithelial cells 1 week later. PVR progression was monitored using fundus photography and optical coherence tomography imaging, and histologic analysis of the retina as an endpoint. We developed a PVR grading scheme tailored for this model. Results: We report that mice that received gas before retinal pigment epithelial injection developed more severe PVR. In the 1 × 10 4 retinal pigment epithelial cell group, after 1 week, 0 of 11 mice in the no gas group developed grade 4 or greater PVR compared with 5 of 13 mice in the SF 6 gas group (P = 0.02); after 4 weeks, 3 of 11 mice in the no gas group developed grade 5 or greater PVR compared with 11 of 14 mice in the SF 6 gas group (P = 0.01). We were able to visualize contractile membranes both on the retinal surface as well as within the vitreous of PVR eyes, and demonstrated through immunohistochemical staining that these membranes expressed fibrotic markers alpha smooth muscle actin, vimentin, and fibronectin, as well as other markers known to be found in human PVR membranes. Conclusions: This mouse PVR model is reproducible and mimics aspects of PVR pathology reported in the rabbit PVR model and human PVR. The major advantage is the ability to study PVR development in different genetic backgrounds to further elucidate aspects of PVR pathogenesis. Additionally, large-scale experiments for testing pharmacologic agents to treat and prevent PVR progression is more feasible compared with other animal models. Translational Relevance: This model will provide a platform for screening potential drug therapies to treat and prevent PVR, as well as elucidate different molecular pathways involved in PVR pathogenesis.

Salinomycin inhibits proliferative vitreoretinopathy formation in a mouse model

“…PVR was induced in one eye of the mouse as previously reported [ 20 ]. Briefly, mice were anesthetized by intraperitoneal injection of 100mg/kg ketamine (Par Pharmaceuticals, Chestnut Ridge, NY) and 10 mg/kg xylazine (Akorn Inc, Lake Forest, IL).…”

“…These injections were done in groups of 5 eyes per treatment (experimental replication) and at different times (biological replication). All PVR grades were determined using the Mouse PVR Grading Scale [ 20 ]. Any eyes that had cataracts or other media opacities which prevented retinal imaging were not included in the analysis.…”

“…10-micron sections were cut using a Microm HM310. Hematoxylin and eosin (H+E) staining was performed as described previously [ 20 ].…”

“…Similar differences were seen for Vimentin and GFAP proteins, which are expressed in activated glial cells, fibroblasts, and myofibroblasts ( Fig 3C and 3D), https://doi.org/10.1371/journal.pone.0243626.g002 Table 1. A summary of the key characteristics that define each grade of the mouse PVR model used in this study [20].…”

“…Based on these studies, we hypothesized that SNC would attenuate PVR formation in vivo . Here, we report that SNC is effective at reducing PVR formation in a mouse model of PVR [ 20 ]. Our results show that intravitreal SNC treatment inhibits development of PVR after 4 weeks compared to controls in vivo , demonstrating that SNC is a promising potential therapeutic agent for PVR that warrants further study.…”