de Lemos Luisa, Antas Pedro, Ferreira Inês S, Santos Inês Paz, Felgueiras Beatriz, Gomes Catarina M, Brito Catarina, Seabra Miguel C, Tenreiro Sandra
iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Rua Camara Pestana, 6, Lisbon, Portugal.
iBET, Instituto de Biologia Experimental E Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal.
In Vitro Model. 2024 Mar 25;3(1):33-48. doi: 10.1007/s44164-024-00068-1. eCollection 2024 Feb.
Diabetic retinopathy (DR) is a complication of diabetes and a primary cause of visual impairment amongst working-age individuals. DR is a degenerative condition in which hyperglycaemia results in morphological and functional changes in certain retinal cells. Existing treatments mainly address the advanced stages of the disease, which involve vascular defects or neovascularization. However, it is now known that retinal neurodegeneration and inflammation precede these vascular changes as early events of DR. Therefore, there is a pressing need to develop a reliable human in vitro model that mimics the early stage of DR to identify new therapeutic approaches to prevent and delay its progression.
Here, we used human-induced pluripotent stem cells (hiPSCs) differentiated into three-dimensional (3D) retinal organoids, which resemble the complexity of the retinal tissue. Retinal organoids were subjected to high-glucose conditions to generate a model of early DR.
Our model showed well-established molecular and cellular features of early DR, such as (i) loss of retinal ganglion and amacrine cells; (ii) glial reactivity and inflammation, with increased expression of the vascular endothelial-derived growth factor () and interleukin-1β (), and monocyte chemoattractant protein-1 (MCP-1) secretion; and (iii) increased levels of reactive oxygen species accompanied by activation of key enzymes involved in antioxidative stress response.
The data provided highlight the utility of retinal organoid technology in modelling early-stage DR. This offers new avenues for the development of targeted therapeutic interventions on neurodegeneration and inflammation in the initial phase of DR, potentially slowing the disease's progression.
The online version contains supplementary material available at 10.1007/s44164-024-00068-1.
糖尿病视网膜病变（DR）是糖尿病的一种并发症，是工作年龄人群视力损害的主要原因。DR是一种退行性疾病，其中高血糖会导致某些视网膜细胞发生形态和功能变化。现有治疗方法主要针对该疾病的晚期阶段，这些阶段涉及血管缺陷或新生血管形成。然而，现在已知视网膜神经退行性变和炎症在这些血管变化之前就作为DR的早期事件出现。因此，迫切需要开发一种可靠的体外人类模型来模拟DR的早期阶段，以确定预防和延缓其进展的新治疗方法。
在这里，我们使用分化为三维（3D）视网膜类器官的人诱导多能干细胞（hiPSC），其类似于视网膜组织的复杂性。将视网膜类器官置于高糖条件下以生成早期DR模型。
我们的模型显示出早期DR成熟的分子和细胞特征，例如：（i）视网膜神经节细胞和无长突细胞的丢失；（ii）神经胶质反应性和炎症，血管内皮生长因子（）和白细胞介素-1β（）表达增加，以及单核细胞趋化蛋白-1（MCP-1）分泌；（iii）活性氧水平升高，同时伴有参与抗氧化应激反应的关键酶的激活。
提供的数据突出了视网膜类器官技术在模拟早期DR方面的实用性。这为在DR初始阶段针对神经退行性变和炎症开发靶向治疗干预措施提供了新途径，有可能减缓疾病进展。
在线版本包含可在10.1007/s44164-024-00068-1获取的补充材料。
