Biology subjects

Buikema, J. W.

Publications and source records attributed to Buikema, J. W..

3 recordsLinked to original sources

bioRxiv2026

Marfan Patient iPSC-Derived Endothelial Cells Carrying FBN1 Variants Reveal Endothelial Dysfunction

Marfan syndrome (MFS) is an inherited connective tissue disorder caused by pathogenic variants in FBN1, encoding fibrillin-1, with life-threatening aortic complications arising in part from endothelial cell (EC) dysfunction. To study this in a human model, we generated hiPSC-derived ECs from three MFS patients (iMFS-ECs). We show that iMFS-ECs recapitulate known disease phenotypes, including impaired alignment in the direction of flow. Moreover, we found that iMFS-ECs do not recover from TNF--induced loss of barrier integrity, due to sustained EC contractility. iMFS-ECs exhibited TNF--induced ICAM1 upregulation and NF-{kappa}B activation comparable to healthy donor-derived hiPSC-ECs by bulk RNA-seq, while expression of genes linked to cytoskeletal arrangements, cell signaling and ECM remodeling were dysregulated. In conclusion, we show that hiPSC derived ECs can serve as a model to investigate MFS pathology. These findings establish a human iPSC platform for MFS endothelial research and suggest impaired inflammatory resolution as a novel therapeutic target.

cell biology↗

bioRxiv2025

Vessel-on-Chip Model Of The Microcirculation In Abdominal Aortic Aneurysms

Abdominal aortic aneurysms (AAA) are pathological dilations of the abdominal aorta. To date, surgical intervention is the only option for managing large AAAs, with no pharmacological therapies to prevent growth of small aneurysms. A current limitation in investigating further pharmacological avenues is the translatability of results from animal models, or from patient trials that are limited by co-morbidities and disease severity. To bridge this knowledge gap, we created a novel, patient-specific vessel-on-chip (VoC) model of the microcirculation in AAA (AAA-VoC). We found that co-culture of both C (control)-VSMCs and AAA-patient derived VSMCs with healthy, hiPSC-derived ECs generate lumenized and perfusable microvascular networks. We show that AAA-VoCs are characterized by an enlarged average vascular diameter. We furthermore found that AAA-VSMCs show phenotypical deviations from C- VSMCs after 7 days in co-culture such as increased number and surface area, indicative of a preserved pathological phenotype in our in vitro model. Lastly, we demonstrate that AAA-VoCs showed an increased level of pro-inflammatory cytokine expression over C-VoCs and displayed an impaired endothelial barrier function, resulting in vascular leakage. With this study, we show that AAA-VSMCs affect microvascular networks formed by healthy hiPSC-ECs and that a AAA phenotype is preserved in 3D co-culture, making this model valuable for future studies investigating treatments for AAA.

cell biology↗

bioRxiv2020

Transcriptional regulation profiling reveals disrupted lipid metabolism in failing hearts with a pathogenic phospholamban mutation

BackgroundThe R14del mutation in the phospholamban (PLN) gene is associated with various types of cardiomyopathies and increases the risk of developing life-threatening ventricular arrhythmias. In this study, we focused on a homogeneous Dutch founder cohort of genetic cardiomyopathy due to PLN R14del mutation and aimed to study the influence of epigenetic changes from a multi-dimensional perspective. ResultsUsing cardiac tissue of PLN R14del patients and donors, we identified differentially acetylated promoters and enhancers (H3K27ac ChIPseq), annotated enriched transcription factor (TF) binding motifs located in those regions, and identified differentially expressed genes (RNA-seq). In line with the fibrofatty replacement in PLN R14del hearts at the histological level, our integrative analysis detected the downregulation of key TF regulators in fatty acid oxidation (FAO) metabolisms and their downstream target in PLN R14del hearts as compared to controls. We further examined heart tissue using immunofluorescence staining (IF) and to confirm the mitochondrial lipid abnormalities in the PLN R14del hearts. Furthermore, we observed the accumulation and deformation of lipid droplets and a disrupted morphology of mitochondria, the key organelle where FAO takes place, in PLN R14del heart using transmission electron microscopy (TEM). ConclusionUsing multi-omics approaches, we successfully obtained a unique list of chromatin regions and genes, including TF-coding genes, which played important roles in the metabolism-related signalling in PLN R14del hearts.

genomics↗