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

Philipp C. Hauger, Gabija Danilinaite, Leonardo Spagnolello, Carsten Künne, Max C. Overboom, Jan Willem Buikema, Vivian de Waard, Peter L. Hordijk

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-α-induced loss of barrier integrity, due to sustained EC contractility. iMFS-ECs exhibited TNF-α-induced ICAM1 upregulation and NF-κB 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.