期刊
STEM CELL REPORTS
卷 16, 期 9, 页码 2305-2319出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2021.07.011
关键词
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资金
- National Key R&D Program of China [2017YFA0103700]
- National Natural Science Foundation of China [81870175, 81922006, 31571528]
- Natural Science Foun-dation of Zhejiang Province [LR15H020001]
- Na-tional Natural Science Foundation of China [81670639, 81670640]
- Beijing Natural Science Foundation [7192207, 7172215]
- Zhejiang University Education Foundation ZJU-Stanford Collaboration Fund
The study found that dysfunction of endothelial cells may be a central pathogenesis in atypical hemolytic uremic syndrome (aHUS), and using induced pluripotent stem cell-derived endothelial cell model can provide insights into the molecular mechanisms of the disease. The activation of the p38 MAPK signaling pathway could be a potential therapeutic target for aHUS treatment.
Atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high morbidity and mortality. Existing evidence suggests that the central pathogenesis to aHUS might be endothelial cell damage. Nevertheless, the role of endothelial cell alterations in aHUS has not been well characterized and the underlying mechanisms remain unclear. Utilizing an induced pluripotent stem cell-derived endothelial cell (iPSC-EC) model, we showed that anti-complement factor H autoantibody-associated aHUS patient-specific iPSC-ECs exhibited an intrinsic defect in endothelial functions. Stimulation using aHUS serums exacerbated endothelial dysfunctions, leading to cell apoptosis in iPSC-ECs. Importantly, we identified p38 as a novel signaling pathway contributing to endothelial dysfunctions in aHUS. These results illustrate that iPSC-ECs can be a reliable model to recapitulate EC pathological features, thus providing a unique platform for gaining mechanistic insights into EC injury in aHUS. Our findings highlight that the p38 MAPK signaling pathway can be a therapeutic target for treatment of aHUS.
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