Molins Blanca, Mesquida Marina, Adan Alfredo
Group of Ocular Inflammation: Clinical and Experimental Studies, Institut d'Investigacions Biomèdiques Agustí Pi I Sunyer (IDIBAPS), C/ Sabino de Arana 1, 08028, Barcelona, Spain.
Group of Ocular Inflammation: Clinical and Experimental Studies, Institut d'Investigacions Biomèdiques Agustí Pi I Sunyer (IDIBAPS), C/ Sabino de Arana 1, 08028, Barcelona, Spain; Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Prog Retin Eye Res. 2022 Jul 12:101097. doi: 10.1016/j.preteyeres.2022.101097.
Alterations of the junctional complex of the outer blood-retinal barrier (oBRB), which is integrated by the close interaction of the retinal pigment epithelium, the Bruch's membrane, and the choriocapillaris, contribute to the loss of neuronal signalling and subsequent vision impairment in several retinal inflammatory disorders such as age-related macular degeneration and diabetic retinopathy. Reductionist approaches into the mechanisms that underlie such diseases have been hindered by the absence of adequate in vitro models using human cells to provide the 3D dynamic architecture that enables expression of the in vivo phenotype of the oBRB. Conventional in vitro cell models are based on 2D monolayer cellular cultures, unable to properly recapitulate the complexity of living systems. The main drawbacks of conventional oBRB models also emerge from the cell sourcing, the lack of an appropriate Bruch's membrane analogue, and the lack of choroidal microvasculature with flow. In the last years, the advent of organ-on-a-chip, bioengineering, and stem cell technologies is providing more advanced 3D models with flow, multicellularity, and external control over microenvironmental properties. By incorporating additional biological complexity, organ-on-a-chip devices can mirror physiologically relevant properties of the native tissue while offering additional set ups to model and study disease. In this review we first examine the current understanding of oBRB biology as a functional unit, highlighting the coordinated contribution of the different components to barrier function in health and disease. Then we describe recent advances in the use of pluripotent stem cells-derived retinal cells, Bruch's membrane analogues, and co-culture techniques to recapitulate the oBRB. We finally discuss current advances and challenges of oBRB-on-a-chip technologies for disease modelling.
外层血视网膜屏障（oBRB）的连接复合体发生改变，该屏障由视网膜色素上皮、布鲁赫膜和脉络膜毛细血管紧密相互作用整合而成，在年龄相关性黄斑变性和糖尿病视网膜病变等几种视网膜炎症性疾病中，会导致神经元信号传导丧失及随后的视力损害。由于缺乏使用人类细胞的适当体外模型来提供能够表达oBRB体内表型的三维动态结构，对这些疾病潜在机制的简化研究方法受到了阻碍。传统的体外细胞模型基于二维单层细胞培养，无法恰当地重现生命系统的复杂性。传统oBRB模型的主要缺点还源于细胞来源、缺乏合适的布鲁赫膜类似物以及缺乏有血流的脉络膜微血管系统。在过去几年中，芯片器官、生物工程和干细胞技术的出现提供了更先进的具有血流、多细胞性以及对微环境特性进行外部控制的三维模型。通过纳入更多的生物学复杂性，芯片器官装置可以反映天然组织的生理相关特性，同时提供额外的设置来模拟和研究疾病。在本综述中，我们首先审视目前对oBRB生物学作为一个功能单元的理解，强调不同组分在健康和疾病状态下对屏障功能的协同作用。然后我们描述在使用多能干细胞衍生的视网膜细胞、布鲁赫膜类似物和共培养技术来重现oBRB方面的最新进展。我们最后讨论用于疾病建模的芯片上oBRB技术的当前进展和挑战。
