Zou Keyi, Li Xue, Ren Bibo, Cheng Fu, Ye Jian, Ou Zelin
Department of Ophthalmology, The Third Hospital Affiliated to the Third Military Medical University Department of Ophthalmology, Chongqing, 400042, China.
College of Biomass Science and Engineering, Sichuan University, Chengdu, 610065, China.
J Transl Med. 2025 Mar 11;23(1):310. doi: 10.1186/s12967-025-06320-w.
Proliferative diabetic retinopathy (PDR) is among the primary causes of blindness in individuals with diabetes. Elevated lactate levels have been identified as a critical biomarker associated with the prognosis of PDR. While significant lactate accumulation has been observed in the vitreous fluid of PDR patients, the detailed pathways through which lactate impacts pathological neovascularization remain insufficiently elucidated.
The study employed single-cell RNA sequencing (scRNA-seq) to identify and characterize lactate-associated cell type in PDR patients. Key gene expression profiles and molecular pathways associated with lactate metabolism were analyzed. In vitro experiments were conducted using microglial cell cultures treated with high-glucose conditions (50 mM) to assess the induction of lactate metabolism-related genes. Additionally, an oxygen-induced retinopathy (OIR) mouse model was used to evaluate the impact of abemaciclib, an FDA-approved proliferation inhibitor, on retinal neovascularization.
To the best of our knowledge, this investigation is the first to delineate a novel microglial subset, designated as MKI67 microglia, distinguished by robust upregulation of genes implicated in lactate metabolic processes and proliferation, such as MKI67, PARK7 and LDHA, as well as a pronounced enrichment of glycolysis-associated molecular pathways. This unique cell type promotes angiogenesis by interacting with endothelial cells via secreted phosphoprotein 1 (SPP1)-Integrin alpha 4 (ITGA4) signaling. In vitro experiments have shown the use of 50 mM high glucose to simulate microglia in PDR environment and observe its promotion of vascular proliferation. In the in vivo OIR model, treatment with abemaciclib, a FDA-approved proliferation inhibitor, significantly reduced neovascularization.
The identification of MKI67 microglia as a cell type strongly associated with lactate metabolism provides a novel perspective on the mechanisms underlying PDR onset. These findings expand our understanding of the cellular and metabolic dynamics in PDR, emphasizing potential implications for targeted therapeutic interventions.
增殖性糖尿病视网膜病变（PDR）是糖尿病患者失明的主要原因之一。乳酸水平升高已被确定为与PDR预后相关的关键生物标志物。虽然在PDR患者的玻璃体液中观察到显著的乳酸积累，但乳酸影响病理性新生血管形成的详细途径仍未得到充分阐明。
本研究采用单细胞RNA测序（scRNA-seq）来识别和表征PDR患者中与乳酸相关的细胞类型。分析了与乳酸代谢相关的关键基因表达谱和分子途径。使用高糖条件（50 mM）处理的小胶质细胞培养物进行体外实验，以评估乳酸代谢相关基因的诱导情况。此外，使用氧诱导视网膜病变（OIR）小鼠模型来评估美国食品药品监督管理局（FDA）批准的增殖抑制剂阿贝西利对视网膜新生血管形成的影响。
据我们所知，本研究首次描绘了一种新的小胶质细胞亚群，命名为MKI67小胶质细胞，其特征是参与乳酸代谢过程和增殖的基因（如MKI67、PARK7和LDHA）强烈上调，以及糖酵解相关分子途径的显著富集。这种独特的细胞类型通过分泌磷蛋白1（SPP1）-整合素α4（ITGA4）信号与内皮细胞相互作用来促进血管生成。体外实验表明，使用50 mM高糖模拟PDR环境中的小胶质细胞，并观察到其促进血管增殖。在体内OIR模型中，使用FDA批准的增殖抑制剂阿贝西利治疗可显著减少新生血管形成。
将MKI67小胶质细胞鉴定为与乳酸代谢密切相关的细胞类型，为PDR发病机制提供了新的视角。这些发现扩展了我们对PDR细胞和代谢动态的理解，强调了对靶向治疗干预的潜在意义。
