期刊
STEM CELL REPORTS
卷 17, 期 7, 页码 1536-1545出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2022.05.022
关键词
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资金
- Netherlands Organization for Health Research and Development (ZonMw) [PTO 446002501]
- CVON-PHAEDRA Impact
- NWO Gravitation project - Ministry of Education, Culture and Science of the government of the Netherlands [024.003.001]
- European Research Council [ERCAdG 323182 STEMCARDIOVASC]
- Association Maladie de Rendu-Osler (AMRO)
- Kees Westermann Fund
- European Union's Horizon 2020 research and innovation program under Marie Sklodowska Curie grant [707404]
In this study, the researchers generated hiPSCs from a patient with rare mosaic HHT1 and successfully derived both diseased and healthy hiPSCs. They found that HHT1 blood vessels displayed defects in vascular organization when grown in 3D organ-on-chip devices, which were not evident in conventional 2D assays.
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent stem cells (hiPSCs) from a patient with rare mosaic HHT1 with tissues containing both mutant (ENG(c.)(1678C>)(T)) and normal cells, enabling derivation of isogenic diseased and healthy hiPSCs, respectively. We showed reduced ENG expression in HHT1 endothelial cells (HHT1-hiPSC-ECs), reflecting haploinsufficiency. HHT1(c.)(1678C)(>T)-hiPSC-ECs and the healthy isogenic control behaved similarly in two-dimensional (2D) culture, forming functionally indistinguishable vascular networks. However, when grown in 3D organ-on-chip devices under microfluidic flow, lumenized vessels formed in which defective vascular organization was evident: interaction between inner ECs and surrounding pericytes was decreased, and there was evidence for vascular leakage. Organs on chip thus revealed features of HHT in hiPSC-derived blood vessels that were not evident in conventional 2D assays.
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