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.

静脉畸形（VMs）是一种常见的血管畸形，通常归因于静脉内皮细胞（VECs）中的非遗传性体细胞突变。由于缺乏稳健的VM疾病模型，新药的发现受到了阻碍。在本研究中，我们将杂合突变引入了诱导多能干细胞（iPSCs），并制定了一套生成iVECs的稳健方案。该方案涉及通过维甲酸信号通路对细胞周期动态的精心调控。突变后的iVECs表现出异常的TIE2信号传导，并在体内形成扩张的血管，从而再现了VMs的表型特征。此外，通过深度神经网络和高通量DRUG-Seq方法，我们进行了药物筛选，并鉴定出Bosutinib，该药物能够有效挽救体外和体内的疾病表型。总之，通过基因组编辑和干细胞技术，我们生成了VM模型，从而促进了新型潜在治疗药物的开发。