Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
Department of Comparative Pathobiology, Tufts University, Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States.
Invest Ophthalmol Vis Sci. 2023 Dec 1;64(15):39. doi: 10.1167/iovs.64.15.39.
Proliferative vitreoretinopathy (PVR) is the most common cause of failure of surgically repaired rhegmatogenous retinal detachment (RRD). Chemically induced and cell injection PVR models do not fully simulate the clinical characteristics of PVR in the post-RRD context. There is an unmet need for translational models in which to study mechanisms and treatments specific to RRD-PVR.
RRD was induced in adult Dutch Belted rabbits. Posterior segments were fixed or processed for RNA sequencing at 6 hours and 2, 7, 14, and 35 days after induction. Histochemical staining and immunolabeling for glial fibrillary acidic protein, alpha smooth muscle actin, vascular endothelial growth factor receptor 2, CD68, and RPE 65 kDa protein were performed, and labeling intensity was scored. Single cell RNA sequencing was performed.
Acute histopathological changes included intravitreal and intraretinal hemorrhage, leukocytic vitritis, chorioretinitis, and retinal rarefaction. Chronic lesions showed retinal atrophy, gliosis, fibrotic subretinal membranes, and epiretinal fibrovascular proliferation. Fibrillar collagen was present in the fibrocellular and fibrovascular membranes in chronic lesions. Moderate to strong labeling of glia and vasculature was detected in chronic lesions. At day 14, most cells profiled by single cell sequencing were identified as Mϋller glia and microglia, consistent with immunolabeling. Expression of several fibrillar collagen genes was upregulated in chronic lesions.
Histological and transcriptional features of this rabbit model simulate important features of human RRD-PVR, including the transition to chronic intraretinal and periretinal fibrosis. This animal model of RRD with features of PVR will enable further research on targeted treatment interventions.
增生性玻璃体视网膜病变（PVR）是手术修复裂孔源性视网膜脱离（RRD）失败的最常见原因。化学诱导和细胞注射 PVR 模型不能完全模拟 RRD 后 PVR 的临床特征。目前迫切需要一种能够研究针对 RRD-PVR 的特定机制和治疗方法的转化模型。
在成年荷兰兔中诱导 RRD。在诱导后 6 小时以及 2、7、14 和 35 天，对后节进行固定或进行 RNA 测序处理。进行胶质纤维酸性蛋白、α平滑肌肌动蛋白、血管内皮生长因子受体 2、CD68 和 RPE 65kDa 蛋白的组织化学染色和免疫标记，并对标记强度进行评分。进行单细胞 RNA 测序。
急性组织病理学变化包括玻璃体内和视网膜内出血、白细胞性玻璃体炎、脉络膜炎和视网膜稀疏。慢性病变表现为视网膜萎缩、胶质增生、纤维状视网膜下膜和视网膜前纤维血管增生。在慢性病变的纤维细胞和纤维血管膜中存在纤维状胶原蛋白。在慢性病变中检测到中等至强的胶质和脉管系统标记。在第 14 天，单细胞测序鉴定的大多数细胞被鉴定为 Muller 胶质细胞和小胶质细胞，与免疫标记一致。在慢性病变中，几种纤维状胶原蛋白基因的表达上调。
该兔模型的组织学和转录特征模拟了人类 RRD-PVR 的重要特征，包括向慢性视网膜内和视网膜周围纤维化的转变。这种具有 PVR 特征的 RRD 动物模型将能够进一步研究针对目标治疗干预的研究。
