Patient-specific iPSC-derived ECs identify QKI-7 as a key regulator of endothelial dysfunction and potential therapeutic target in diabetes.

Authors

Victoria A Cornelius, Jenna Fulton, Clare Donaghy, Stuart McKeown, Hojjat Naderi-Meshkin, Shu-Dong Zhang, Wiwit Ananda Wahyu Setyaningsih, Andrew Yacoub, Anna Zampetaki, Alan W Stitt, Noemi Lois, David J Grieve, Andriana Margariti

Published in

Stem cells translational medicine. Volume 15. Issue 8. Jul 20, 2026.

Abstract

Diabetic vascular complications remain a major cause of morbidity and mortality, yet the molecular mechanisms underlying endothelial dysfunction in diabetes remain incompletely understood. Endothelial dysfunction is a key contributor to vascular pathology, and patient-derived induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) provide a human platform to investigate disease-associated endothelial phenotypes under controlled conditions. Here, we identify the RNA-binding protein Quaking-7 (QKI-7) as a key regulatory factor associated with endothelial dysfunction in patient-derived iPSC-ECs. Using cells derived from diabetic and non-diabetic donors maintained under standard culture conditions, we demonstrate that elevated QKI-7 expression is associated with reduced expression of endothelial homeostatic genes (COL4A2, JUN, TMEM184A, and PPP1R15A) and impaired angiogenic capacity, including reduced tube formation. Importantly, these findings were further validated in three-dimensional blood vessel organoid models, supporting the relevance of QKI-7-associated endothelial phenotypes in a more physiologically complex vascular system. Connectivity mapping identified FDA-approved compounds, including simvastatin, halcinonide, and retinoic acid, as potential modulators of QKI-7-associated pathways. Functional validation in iPSC-ECs demonstrated that these compounds reduce QKI-7 expression and improve endothelial functional readouts. Together, these findings identify QKI-7 as a regulatory node associated with endothelial dysfunction in patient-derived iPSC-ECs and highlight the utility of human iPSC-based vascular models for identifying candidate therapeutic strategies. While these models capture endothelial phenotypes associated with diabetic donor origin, further studies in more complex in vivo systems will be required to establish causal relevance to vascular disease.

PMID:
42560887
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.

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