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bioRxiv · 10.64898/2026.08.20.745919

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

Hauger, P. C.·Danilinaite, G.·Spagnolello, L.·Kuenne, C.·Overboom, M. C.·Buikema, J. W.·de Waard, V.·Hordijk, P. L.
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Abstract

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.

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Hauger, P. C., Danilinaite, G., Spagnolello, L., Kuenne, C., Overboom, M. C., Buikema, J. W., de Waard, V., Hordijk, P. L.. 2026-08-21. Marfan Patient iPSC-Derived Endothelial Cells Carrying FBN1 Variants Reveal Endothelial Dysfunction. https://doi.org/10.64898/2026.08.20.745919

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