Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, D-48149, Münster, Germany.
Bioinformatics Service Unit, Max Planck Institute for Molecular Biomedicine, D-48149, Münster, Germany.
Nat Commun. 2024 Apr 3;15(1):2539. doi: 10.1038/s41467-024-46300-0.
Cell segregation allows the compartmentalization of cells with similar fates during morphogenesis, which can be enhanced by cell fate plasticity in response to local molecular and biomechanical cues. Endothelial tip cells in the growing retina, which lead vessel sprouts, give rise to arterial endothelial cells and thereby mediate arterial growth. Here, we have combined cell type-specific and inducible mouse genetics, flow experiments in vitro, single-cell RNA sequencing and biochemistry to show that the balance between ephrin-B2 and its receptor EphB4 is critical for arterial specification, cell sorting and arteriovenous patterning. At the molecular level, elevated ephrin-B2 function after loss of EphB4 enhances signaling responses by the Notch pathway, VEGF and the transcription factor Dach1, which is influenced by endothelial shear stress. Our findings reveal how Eph-ephrin interactions integrate cell segregation and arteriovenous specification in the vasculature, which has potential relevance for human vascular malformations caused by EPHB4 mutations.
细胞分离使得在形态发生过程中具有相似命运的细胞进行区室化，而细胞命运可塑性可以响应局部分子和生物力学线索增强这种分区化。在生长中的视网膜中，引导血管芽的内皮尖端细胞产生动脉内皮细胞，从而介导动脉生长。在这里，我们结合了细胞类型特异性和诱导型小鼠遗传学、体外流动实验、单细胞 RNA 测序和生物化学方法，表明 Ephrin-B2 与其受体 EphB4 之间的平衡对于动脉特化、细胞分选和动静脉模式形成至关重要。在分子水平上，EphB4 缺失后 Ephrin-B2 功能的升高增强了 Notch 通路、VEGF 和转录因子 Dach1 的信号反应，而这种反应受到内皮切应力的影响。我们的研究结果揭示了 Eph-ephrin 相互作用如何整合血管中的细胞分离和动静脉特化，这对于由 EphB4 突变引起的人类血管畸形具有潜在的相关性。
