Data_Sheet_1_Single-cell transcriptome reveals diversity of Müller cells with different metabolic-mitochondrial signatures in normal and degenerated macula.CSV

Müller cell is the most abundant glial cell in mammalian retina, supporting the functions of photoreceptors and other retinal neurons via maintaining environmental homeostasis. In response to injury and/or neuronal degeneration, Müller cells undergo morphological and functional alternations, known as reactive gliosis documented in multiple retinal diseases, including age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy, and traumatic retinal detachment. But the functional consequences of Müller glia cell reactivation or even the regulatory networks of the retinal gliosis are still controversial. In this study, we reveal different subpopulations of Müller cells with distinct metabolic-mitochondrial signatures by integrating single cell transcriptomic data from Early AMD patients and healthy donors. Our results show that a portion of Müller cells exhibits low mitochondrial DNA (mtDNA) expressions, reduced protein synthesis, impaired homeostatic regulation, decreased proliferative ability but enhanced proangiogenic function. Interestingly, the major alternation of Müller cells in Early AMD retina is the change of subpopulation abundance, rather than generation of new subcluster. Transcription factor enrichment analysis further highlights the key regulators of metabolic-mitochondrial states of Müller glias in Early AMD patients especially. Our study demonstrates new characteristics of retinal gliosis associated with Early AMD and suggests the possibility to prevent degeneration by intervening mitochondrial functions of Müller cells.

米勒胶质细胞（Müller cell）是哺乳动物视网膜中含量最为丰富的胶质细胞，通过维持视网膜微环境稳态，支持光感受器及其他视网膜神经元的功能。当视网膜受到损伤或神经元发生退行性改变时，米勒胶质细胞会出现形态与功能的改变，这一过程被称为反应性胶质增生，该现象在多种视网膜疾病中均有报道，包括年龄相关性黄斑变性（age-related macular degeneration，AMD）、色素性视网膜炎、糖尿病性视网膜病变以及创伤性视网膜脱离。然而，目前关于米勒胶质细胞激活所产生的功能后果，乃至视网膜胶质增生的调控网络，仍存在争议。本研究通过整合早期AMD患者与健康供体的单细胞转录组数据，揭示了具有独特代谢-线粒体特征的米勒胶质细胞亚群。研究结果显示，部分米勒胶质细胞表现出线粒体DNA（mitochondrial DNA，mtDNA）表达水平降低、蛋白质合成减少、稳态调控受损、增殖能力下降，但促血管生成功能增强的特征。有趣的是，早期AMD患者视网膜中的米勒胶质细胞主要改变为亚群丰度的变化，而非新亚簇的产生。转录因子富集分析进一步明确了早期AMD患者米勒胶质细胞代谢-线粒体状态的关键调控因子。本研究阐明了与早期AMD相关的视网膜胶质增生新特征，并提出通过干预米勒胶质细胞的线粒体功能以延缓视网膜退行性变的可能性。