Defining donor-host interactions to improve photoreceptor replacement therapy

在工业化社会中，光感光感受器的丧失是导致视力损伤和失明的主要原因，临床上还没有确定的治疗方法。供体光感受器移植被认为是一种旨在替代退化的光感受器的一般治疗选择。事实上，最近的技术进步允许在体外产生足够数量的多能干细胞衍生的视网膜有机体中的人类光感受器。首先，体内的临床前研究为移植到视网膜变性动物模型后的一些功能改善提供了证据。然而，目前尚不清楚成功实现结构和功能整合的细胞和分子要求和机制，包括与受体视网膜细胞的连接。此外，尽管光感受器完全丧失是视网膜退行性疾病的最后阶段，但疾病进展的潜在原因和动力学是高度多样化的，导致非常不同的受体环境。因此，基于我们建立的利用人类诱导的多能干细胞来源的光感受器进行临床前移植的管道，将评估移植的整合动力学、内源性视网膜细胞的转录组和蛋白质组的变化以及受体小鼠的不同退化阶段，以确定成功进行光感受器替换的细胞和分子需求。所获得的知识对于确定先决条件以及改变受体环境的潜在目标将是至关重要的，以优化移植物的整合、组织和成熟，最终目标是显著改善不同视网膜病变的视觉感受。

The loss of light-sensing photoreceptors represents the main cause for visual impairment and blindness in industrialized societies with no curative therapy established clinically. Transplantation of donor photoreceptors is discussed as a general treatment option aiming to replace degenerated photoreceptors. Indeed, recent technology progress allows the generation of human photoreceptors within pluripotent stem cell-derived retinal organoids in sufficient amounts in vitro. First pre-clinical studies in vivo provide evidence for some functional improvements after transplantation into animal models of retinal degeneration. However, the cellular and molecular requirements and mechanisms that allow successful structural and functional integration including connectivity with cells of the recipient retina are currently unknown. Additionally, while complete photoreceptor loss is the final stage of retinal degenerative diseases, the underlying causes and the dynamics of disease progression are highly diverse resulting in very heterogenous recipient environments. Therefore, based on our established pre-clinical transplantation pipeline using human induced pluripotent stem cell-derived photoreceptors, integration kinetics of transplants, transcriptome and proteome changes of endogenous retinal cells, as well as different degeneration stages of recipient mice will be assessed to identify cellular and molecular needs for successful photoreceptor replacement. Acquired knowledge will be of utmost importance for defining prerequisites as well as potential targets for modification of the recipient environment to optimize graft integration, organization and maturation with the ultimate goal to significantly improve visual perception within different retinal pathologies.