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

Venous malformations (VMs) are common vascular malformations that usually caused by non-inherited somatic mutation in venous endothelial cells. The effective treatment for VMs has been very limited, with a lack of robust disease models hindering the discovery of new therapeutics. Here, we introduced heterozygous mutation into induced pluripotent stem cells and established a reliable venous endothelial cells differentiation strategy to recapitulate VMs. Moreover, utilizing a deep neural network and a high-throughput DRUG-Seq approach, we performed drug screenings and identified bosutinib as an agent that effectively rescued the disease phenotype in vitro and in vivo. In summary, by leveraging on the genome editing and stem cell technology, we generated a VMs model that enabled the development of precise therapeutic strategies for patients with VMs.