Pan Zihang, Yao Qiyang, Kong Weijing, Ma Xiaojing, Tian Liangliang, Zhao Yun, Zhu Shuntian, Chen Sheng, Sun Mengze, Liu Jiao, Jiang Simin, Ma Jianxun, Liu Qijia, Peng Xiaohong, Li Xiaoxia, Hong Zixuan, Hong Yi, Wang Xue, Liu Jiarui, Zhang Jingjing, Zhang Wei, Sun Bingbing, Pahlavan Sara, Xia Youchen, Shen Weimin, Liu Yuyong, Jiang Wenjian, Xie Zhengwei, Kong Wei, Wang Xi, Wang Kai
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Clinical Stem Cell Research Center, Peking University Third Hospital, Peking University, Beijing 100191, China.
Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Cell Stem Cell. 2025 Feb 6;32(2):227-245.e9. doi: 10.1016/j.stem.2024.10.015. Epub 2024 Nov 22.
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 impedes drug discovery. Here, we devise a robust protocol for the generation of human induced VECs (iVECs) through manipulation of cell-cycle dynamics via the retinoic signaling pathway. We introduce an L914F mutation into the TIE2 gene locus of induced pluripotent stem cells (iPSCs) and show that the mutated iVECs form dilated blood vessels after transplantation into mice, thereby recapitulating the phenotypic characteristics observed in VMs. Moreover, utilizing a deep neural network and a high-throughput digital RNA with perturbation of genes sequencing (DRUG-seq) approach, we perform drug screening and demonstrate that bosutinib effectively rescues the disease phenotype in vitro and in vivo. In summary, by leveraging genome editing and stem cell technology, we generate VM models that enable the development of additional therapeutics.
静脉畸形（VMs）是常见的血管异常，通常归因于静脉内皮细胞（VECs）内非遗传性体细胞突变。缺乏针对VMs的强大疾病模型阻碍了药物研发。在此，我们设计了一种强大的方案，通过视黄酸信号通路操纵细胞周期动力学来生成人诱导VECs（iVECs）。我们将L914F突变引入诱导多能干细胞（iPSCs）的TIE2基因位点，并表明突变的iVECs在移植到小鼠体内后形成扩张的血管，从而重现了VMs中观察到的表型特征。此外，利用深度神经网络和高通量数字RNA基因扰动测序（DRUG-seq）方法，我们进行了药物筛选，并证明波舒替尼在体外和体内均能有效挽救疾病表型。总之，通过利用基因组编辑和干细胞技术，我们生成了能够促进其他治疗方法开发的VM模型。
