Härdtner Carmen, Kumar Anup, Ehlert Carolin A, Vico Tamara Antonela, Starz Christopher, von Ehr Alexander, Krebs Katja, Dufner Bianca, Hoppe Natalie, Stachon Peter, Heidt Timo, Wolf Dennis, von Zur Mühlen Constantin, Grüning Björn, Robbins Clinton S, Maegdefessel Lars, Westermann Dirk, Dederichs Tsai-Sang, Hilgendorf Ingo
Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Hugstetter Street 55, Freiburg, Germany.
Department of Computer Science, Bioinformatics Group, University of Freiburg, Georges-Koehler-Allee 106, Freiburg, Germany.
Atherosclerosis. 2023 Apr;371:1-13. doi: 10.1016/j.atherosclerosis.2023.03.006. Epub 2023 Mar 15.
Atherosclerosis is a systemic and chronic inflammatory disease propagated by monocytes and macrophages. Yet, our knowledge on how transcriptome of these cells evolves in time and space is limited. We aimed at characterizing gene expression changes in site-specific macrophages and in circulating monocytes during the course of atherosclerosis.
We utilized apolipoprotein E-deficient mice undergoing one- and six-month high cholesterol diet to model early and advanced atherosclerosis. Aortic macrophages, peritoneal macrophages, and circulating monocytes from each mouse were subjected to bulk RNA-sequencing (RNA-seq). We constructed a comparative directory that profiles lesion- and disease stage-specific transcriptomic regulation of the three cell types in atherosclerosis. Lastly, the regulation of one gene, Gpnmb, whose expression positively correlated with atheroma growth, was validated using single-cell RNA-seq (scRNA-seq) of atheroma plaque from murine and human.
The convergence of gene regulation between the three investigated cell types was surprisingly low. Overall 3245 differentially expressed genes were involved in the biological modulation of aortic macrophages, among which less than 1% were commonly regulated by the remote monocytes/macrophages. Aortic macrophages regulated gene expression most actively during atheroma initiation. Through complementary interrogation of murine and human scRNA-seq datasets, we showcased the practicality of our directory, using the selected gene, Gpnmb, whose expression in aortic macrophages, and a subset of foamy macrophages in particular, strongly correlated with disease advancement during atherosclerosis initiation and progression.
Our study provides a unique toolset to explore gene regulation of macrophage-related biological processes in and outside the atheromatous plaque at early and advanced disease stages.
动脉粥样硬化是一种由单核细胞和巨噬细胞引发的全身性慢性炎症性疾病。然而，我们对于这些细胞的转录组如何随时间和空间演变的了解有限。我们旨在描述动脉粥样硬化过程中特定部位巨噬细胞和循环单核细胞的基因表达变化。
我们利用载脂蛋白E缺陷小鼠，使其接受为期1个月和6个月的高胆固醇饮食，以模拟早期和晚期动脉粥样硬化。对每只小鼠的主动脉巨噬细胞、腹腔巨噬细胞和循环单核细胞进行批量RNA测序（RNA-seq）。我们构建了一个比较目录，描绘了动脉粥样硬化中三种细胞类型在病变和疾病阶段特异性的转录组调控。最后，使用来自小鼠和人类动脉粥样斑块的单细胞RNA测序（scRNA-seq）验证了一个基因Gpnmb的调控，该基因的表达与动脉粥样瘤生长呈正相关。
三种研究细胞类型之间的基因调控趋同性出奇地低。总体而言，3245个差异表达基因参与了主动脉巨噬细胞的生物学调节，其中不到1%受远处单核细胞/巨噬细胞共同调控。主动脉巨噬细胞在动脉粥样瘤起始阶段最活跃地调节基因表达。通过对小鼠和人类scRNA-seq数据集的互补研究，我们展示了我们目录的实用性，使用选定的基因Gpnmb，其在主动脉巨噬细胞，特别是一部分泡沫巨噬细胞中的表达，与动脉粥样硬化起始和进展过程中的疾病进展密切相关。
我们的研究提供了一个独特的工具集，用于探索疾病早期和晚期动脉粥样斑块内外巨噬细胞相关生物学过程的基因调控。
