An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death

Abstract

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in fibrillin-1, an extracellular matrix protein. To investigate the pathogenesis of aortic aneurysms in MFS, we have generated the first vascular model derived from human induced pluripotent stem cells (hiPSC). Our MFS-hiPSC derived smooth muscle cells (SMC) accurately recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extra-cellular matrix degradation, TGF-β signaling, contraction, and apoptosis; abnormalities are corrected by CRISPR-editing of the fibrillin-1 mutation. TGF-β inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the non-canonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by KLF4. This model has allowed us to dissect the molecular mechanisms of MFS, to identify novel targets for treatment, such as p38 and KLF4, and has provided an innovative human platform for the testing of new drugs.