Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform
Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform
复制标题
DOI：
10.7554/elife.46188
复制
发表时间：
2019-08-27
期刊：
影响因子：
7.7
通讯作者：
Loskill, Peter
中科院分区：
文献类型：
--
作者：
Achberger, Kevin;Probst, Christopher;Loskill, Peter
遗传性和散发性视网膜疾病如Stargardt病、年龄相关性黄斑变性或视网膜色素变性的破坏性影响和不可治愈的性质迫切需要开发新的治疗策略。此外，视网膜毒性的高患病率越来越成为新型靶向治疗剂的问题。迄今为止，眼科药物开发主要依赖于动物模型，其通常不能提供可转化为人类患者的结果。因此，建立复杂的基于人体组织的体外模型至关重要。来源于人胚胎干细胞（hESC）或人诱导多能干细胞（hiPSC）的自形成视网膜类器官（RO）的发现是模拟复杂分层视网膜组织的有前途的方法。然而，RO缺乏血管化，无法再现成熟光感受器和视网膜色素上皮（RPE）的重要生理相互作用。在这项研究中，我们提出了视网膜芯片（RoC），一种新的微生理模型的人视网膜整合超过七种不同的基本视网膜细胞类型来自hiPSCs。它提供了血管样灌注，并使，第一次，重演的成熟感光细胞片段与RPE在体外的相互作用。我们发现，这种相互作用增强了外段样结构的形成和体内样生理过程的建立，如外段吞噬作用和钙动力学。此外，我们证明了适用性的RoC的药物测试，复制视网膜病变的副作用的抗疟疾药物氯喹和抗生素庆大霉素。开发的基于hiPSC的RoC具有促进药物开发的潜力，并为视网膜疾病的潜在病理学提供新的见解。
The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of upmost importance. The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-achip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro. We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases.