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Cell stem cell

Cell stem cell

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

Published:22 November 2024 DOI: 10.1016/j.stem.2024.10.015
Zihang Pan, Qiyang Yao, Kai Wang

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.

Substances (6)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Ascorbic Acid 50-81-7 C6H8O6 1620 suppliers $6.00-$2170.00
Retinoic acid 302-79-4 C20H28O2 858 suppliers $5.00-$1080.00
Polysorbate 20 9005-64-5 C26H50O10 649 suppliers $12.00-$6080.49
Gelatin 9000-70-8 C6H12O6 590 suppliers $22.70-$3510.00
D-Luciferin potassium salt 115144-35-9 C11H9KN2O3S2 351 suppliers $12.00-$4173.50
DAPT 208255-80-5 C23H26F2N2O4 222 suppliers $28.00-$2776.00

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