Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Stem Cell. 2018 Aug 2;23(2):210-225.e6. doi: 10.1016/j.stem.2018.07.011.
The cellular and mechanistic bases underlying endothelial regeneration of adult large vessels have proven challenging to study. Using a reproducible in vivo aortic endothelial injury model, we characterized cellular dynamics underlying the regenerative process through a combination of multi-color lineage tracing, parabiosis, and single-cell transcriptomics. We found that regeneration is a biphasic process driven by distinct populations arising from differentiated endothelial cells. The majority of cells immediately adjacent to the injury site re-enter the cell cycle during the initial damage response, with a second phase driven by a highly proliferative subpopulation. Endothelial regeneration requires activation of stress response genes including Atf3, and aged aortas compromised in their reparative capacity express less Atf3. Deletion of Atf3 reduced endothelial proliferation and compromised the regeneration. These findings provide important insights into cellular dynamics and mechanisms that drive responses to large vessel injury.
内皮细胞对成年大血管的再生机制和细胞学基础的研究一直以来都极具挑战性。通过使用一种可重复的体内主动脉内皮损伤模型，我们结合多色谱系追踪、联体共生和单细胞转录组学，对再生过程中的细胞动力学进行了研究。我们发现，再生是一个由两个不同阶段组成的过程，这两个阶段分别由分化的内皮细胞产生的不同群体所驱动。在初始损伤反应中，与损伤部位相邻的大多数细胞立即重新进入细胞周期，而第二个阶段则由一个高度增殖的亚群驱动。内皮细胞的再生需要激活应激反应基因，包括 Atf3，而在修复能力受损的老年主动脉中，Atf3 的表达水平较低。Atf3 的缺失会减少内皮细胞的增殖并损害再生。这些发现为研究大血管损伤的细胞动力学和机制提供了重要的见解。
