Abstract
SUMMARYArteries 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 cell fate conversion. Using scRNA-Seq and mouse genetics, we discovered 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. Prior to coronary blood flow, pre-artery cells appeared within the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein specifying transcription factor, Coup-tf2, blocked plexus cells from overcoming the pre-artery threshold through inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independent of blood flow upon the release of COUP-TF2/cell cycle factor-mediated inhibition.
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