Date

Wednesday 23 Sep 2026

Time

15:15 - 15:45

Location

BW0.19

Supervisor

Mario van der Stelt

Jury

Sander van Kasteren

External supervisor

Dr. Jean-Philippe Frimat

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal-dominant small-vessel disease caused by C-terminal truncating mutations in three prime repair exonuclease 1 (TREX1). These mutations are known to cause TREX1 protein mislocalization while maintaining exonuclease activity. However, the molecular mechanisms underlying the disease pathology remain poorly understood. As RVCL-S cells have been shown to be particularly sensitive to inflammatory and genotoxic stress, this study aimed to investigate whether such triggers induce TREX1 expression in endothelial cells in vitro.

Human umbilical vein endothelial cells (HUVECs) and human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) were exposed to various inflammatory and genotoxic triggers, including ionizing radiation (IR), ultraviolet (UV) light, and cytokines. After treatment, TREX1 expression patterns were analysed at the mRNA and protein levels using reverse transcription quantitative PCR (RT-qPCR) and Western blot analyses. In addition, DNA damage and repair kinetics following IR exposure were evaluated by immunostaining.

Results showed TREX1 expression remained remarkably stable in response to the treatments applied and strongly increased only after interferon-β (IFN-β) treatment. This response could be further enhanced by additional exposure to tumour necrosis factor-α (TNF-α). UV exposure may also have increased TREX1 levels, but the window of transcriptional increase was not adequately captured by the applied setup. Results also showed that HUVECs are a useful baseline model for preliminary testing, and hiPSC-ECs showed similar response patterns but with greater sensitivity.

This research provides foundational insights into wild-type TREX1 expression in endothelial cells in vitro after exposure to various inflammatory or genotoxic triggers. These findings can prove useful in future research aimed at bridging the gap between the molecular behaviour of TREX1 and the clinical manifestations of RVCL-S.