Integrative Vascular Biology Laboratory (E.C., J.S., I.H., H.G.), Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
DZHK (German Center for Cardiovascular Research), Berlin, Germany (E.C., J.S., N.H., H.G.).
Circ Res. 2024 Aug 30;135(6):671-684. doi: 10.1161/CIRCRESAHA.124.324868. Epub 2024 Aug 2.
The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart.
Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species.
We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. -lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism.
A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.
冠状动脉的精细图案对于跳动心脏的高代谢活动至关重要。冠状动脉内皮细胞如何协调层次血管重塑并实现动静脉特化在很大程度上仍是未知的。了解图案化冠状动脉的分子和细胞线索对于开发创新的治疗策略以恢复缺血心脏的功能灌注至关重要。
单细胞转录组学和组织学验证用于描绘发育中和成熟的冠状动脉内皮细胞的异质转录状态，重点是发芽内皮细胞和动脉细胞特化。遗传谱系追踪和高分辨率 3 维成像用于描述冠状动脉血管生成发芽的起源和机制，以及对选择性内皮谱系进行命运图谱分析。整合缺血成年小鼠心脏和人类胚胎的单细胞转录组数据，用于评估转录状态在发育、疾病和物种之间的保守性。
我们发现冠状动脉起源于先前经历特定尖端细胞表型的细胞。我们确定了具有不同基因表达谱和调控途径的非重叠心肌内和心外膜尖端细胞群。-谱系追踪证实心肌内尖端细胞选择性地贡献于冠状动脉和心内膜隧道，但不贡献于静脉。值得注意的是，前动脉细胞从发育阶段到成年期都有检测到，对缺血性损伤的反应越来越多，在人类胚胎中也有检测到，这表明尖端细胞到动脉的特化是一种保守的机制。
尖端细胞到动脉的特化机制驱动整个生命周期中心肌内丛和心内膜隧道的动脉化，并在缺血性损伤时被重新激活。不同的发芽程序控制静脉和动脉冠状动脉丛的形成和特化。
