Department of Biology, Stanford University, Stanford, CA, USA.
Program in Biophysics, Stanford University, Stanford, CA, USA.
Nature. 2018 Jul;559(7714):356-362. doi: 10.1038/s41586-018-0288-7. Epub 2018 Jul 4.
Arteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre-existing veins through a poorly understood process of cell fate conversion. Here, using single-cell RNA sequencing and mouse genetics, we show that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein-specifying transcription factor COUP-TF2 (also known as NR2F2) prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors.
动脉和静脉由拮抗的转录程序决定。然而，在发育和再生过程中，新的动脉可以通过一个尚未被充分了解的细胞命运转换过程从现有的静脉中产生。在这里，我们使用单细胞 RNA 测序和小鼠遗传学，表明发育中心脏的静脉细胞经历了早期的细胞命运转换，产生了一个前动脉群体，随后构建了冠状动脉。静脉细胞在亚群细胞跨越转录阈值进入前动脉状态之前，逐渐且同时从静脉命运向动脉命运转变。在冠状动脉血流开始之前，前动脉细胞出现在未成熟的血管丛中，表达成熟的动脉标记物，并减少细胞周期。静脉特异性转录因子 COUP-TF2（也称为 NR2F2）通过诱导细胞周期基因，阻止丛状细胞克服前动脉阈值。因此，静脉衍生的冠状动脉是由前动脉细胞构建的，这些细胞可以在 COUP-TF2 和细胞周期因子介导的抑制释放后独立于血流分化。
