Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations 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 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.

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Publication Details

Journal
Cell stem cell
Published
2024-11-22
DOI
https://doi.org/10.1016/j.stem.2024.10.015
Citations
28
Primary Topic
Lymphatic System and Diseases
Type
article
Field-Weighted Citation Impact
7.91
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article

Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery

Xiaohong Peng, Sheng Chen, Yuyong Liu, Zhengwei Xie et al.
28 citations
Cell stem cell
Lymphatic System and Diseases
7.91
article

Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery

Xiaohong Peng, Sheng Chen, Yuyong Liu, Zhengwei Xie, Sara Pahlavan, Mengze Sun, Shuntian Zhu, You-Chen Xia, Qijia Liu, Jianxun Ma, Weimin Shen, Weijia Kong, Zixuan Hong, Bingbing Sun, Wenjian Jiang, Xiaojing Ma, Zihang Pan, Yun Zhao, Jiao Liu, Xiaoxia Li, Jingjing Zhang, Xue Wang, Weidong Zhang, Xi Wang, Jiarui Liu, Kai Wang, Liangliang Tian, Weijing Kong, Simin Jiang, Qiyang Yao, Hong Yi
article en
28 citations

Abstract

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.

Cell stem cellVol. 32(2)
Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Royan Institute (IR), Academic Center for Education, Culture and Research (IR), Beijing Anzhen Hospital (CN), Second Affiliated Hospital of Nanjing Medical University (CN), Peking University Third Hospital (CN)
Good health and well-being
Openalex Percentile: Top 2%
Lymphatic System and Diseases
7.91
DOIOpen Access PDFOpenAlex
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