iPSC-derived venous endothelial cells for modeling vascular malformation and drug discovery

Venous malformations (VMs) represent prevalent vascular anomalies typically attributed to non-inherited somatic mutations within venous endothelial cells (VECs). The lack of robust disease models for VMs impeded the discovery of new drugs. Here, we implemented heterozygous mutation into iPSCs and devised a robust protocol for the generation of iVECs. This protocol involved the deliberate manipulation of cell cycle dynamics mediated through the retinoic signaling pathway. The mutated iVECs exhibited aberrant TIE2 signaling and formed dilated blood vessels in vivo, thereby recapitulating the phenotypic characteristics observed in VMs. Moreover, utilizing a deep neural network and a high-throughput DRUG-Seq approach, we performed drug screening and identified Bosutinib that effectively rescued the disease phenotype in vitro and in vivo. In summary, by leveraging genome editing and stem cell technology, we generated VM models that enabled the development of new potential therapeutics.