Lung endothelial cells (MLECs) from knock-in mouse model with or without the causative HGPS LmnaG609G mutation. Lung endothelial cells (MLECs) from knock-in mouse model with or without the causative HGPS LmnaG609G mutation

Vascular dysfunction is one of the typical characteristics of aging, but its contributing roles to systemic aging and the therapeutic potential is lacking experimental evidence. Accumulating data suggest that the mechanisms underlying aging are similar to those governing Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disease, in which affected patients succumb to cardiovascular diseases (CVDs). Here, we generated a knock-in mouse model with the causative HGPS LmnaG609G mutation, called progerin. We crossed Lmnaf/f mice with a Tie2-Cre line to get Lmnaf/f;TC mice, which exhibit defective microvasculature and neovascularization, accelerated aging and shortened lifespan. Single-cell transcriptomic analysis of murine lung endothelial cells (MLECs) revealed a significant upregulation of inflammatory response. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction. Overall design: We isolated CD31+ MLECs from three pairs of LmnaG609G/G609G (G609G) and Lmnaf/f (Flox) mice by FACS

血管功能障碍是衰老的典型特征之一，但其对系统性衰老的促发作用及治疗潜力尚缺乏实验证据支撑。越来越多的研究表明，衰老的核心机制与早老症（Hutchinson-Gilford progeria syndrome, HGPS）——一种早发性衰老疾病——的致病机制高度相似，该病患者最终会死于心血管疾病（cardiovascular diseases, CVDs）。本研究构建了携带致病HGPS突变LmnaG609G的敲入小鼠模型，该突变可表达早老素（progerin）。我们将Lmnaf/f小鼠与Tie2-Cre工具鼠杂交，获得Lmnaf/f;TC小鼠，该模型小鼠表现出微血管结构与血管新生功能缺陷、衰老加速以及寿命缩短的表型。对小鼠肺内皮细胞（murine lung endothelial cells, MLECs）进行单细胞转录组分析后发现，其炎症应答通路存在显著上调。上述实验数据证实，内皮功能障碍是系统性衰老的核心诱因，并提示基因疗法有望成为临床治疗HGPS及衰老相关性血管功能障碍的潜在策略。实验整体设计：本研究通过荧光激活细胞分选术（Fluorescence-Activated Cell Sorting, FACS），从3对LmnaG609G/G609G（简称G609G）与Lmnaf/f（简称Flox）小鼠体内分离得到CD31阳性的小鼠肺内皮细胞。