Endothelial Cell Senescence in Marfan Syndrome: Pathogenesis and Therapeutic Potential of TGF-β Pathway Inhibition.

BACKGROUND

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the Fibrillin-1 gene, which encodes the extracellular matrix protein fibrillin-1. Patients with MFS are predisposed to aortic aneurysms and dissections, significantly contributing to mortality. Emerging evidence suggests that endothelial cell (EC) senescence plays a critical role in the pathogenesis of aortic aneurysms in MFS. This study aims to elucidate the role of EC senescence in the development of aortic aneurysms in MFS using a vascular model derived from human induced pluripotent stem cells.

METHODS AND

RESULTS

We generated human induced pluripotent stem cells lines from 2 patients with MFS carrying specific Fibrillin-1 mutations and differentiated these into ECs. These MFS-hiPSC-derived ECs were characterized using immunofluorescence, reverse transcription-quantitative polymerase chain reaction, and Western blotting. Functional assays including cell proliferation, scratch wound, tube formation, NO content detection, and senescence-associated β-galactosidase staining were conducted. RNA sequencing was performed to elucidate underlying signaling pathways, and pharmacological inhibition of the transforming growth factor-beta pathway was assessed for its therapeutic potential. MFS-hiPSC-derived ECs recapitulated the pathological features observed in Marfan aortas, particularly pronounced cellular senescence, decreased cell proliferation, and abnormal transforming growth factor-beta and NF-κB signaling. These senescent ECs exhibited diminished proliferative and migratory capacities, reduced NO signaling, increased production of inflammatory cytokines, and attenuated responses to inflammatory stimuli. Importantly, senescence and dysfunction in MFS-hiPSCderived ECs were ameliorated by transforming growth factor-beta signaling pathway inhibitor, SB-431542, suggesting a potential therapeutic strategy.

CONCLUSIONS

This study highlights the pivotal role of endothelial cell senescence in the pathogenesis of aortic aneurysms in MFS. Our human induced pluripotent stem cells-based disease model provides new insights into the disease mechanisms and underscores the potential of targeting the transforming growth factor-beta pathway to mitigate endothelial dysfunction and senescence, offering a promising therapeutic avenue for MFS.