An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death
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Granata, A., Serrano, F., Bernard, W., McNamara, M., Low, L., Sastry, P., & Sinha, S. (2016). An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nature Genetics https://doi.org/10.1038/ng.3723
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.
This work was supported by Evelyn Trust, the NIHR Cambridge Biomedical Research Centre and the British Heart Foundation (FS/13/29/30024, RM/l3/3/30159, FS/11/77/29327).
Wellcome Trust (097922/Z/11/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819/1415/06 /07 /12 /10)
British Heart Foundation (FS/11/77/29327)
British Heart Foundation (RG/17/5/32936)
British Heart Foundation (FS/13/29/30024)
External DOI: https://doi.org/10.1038/ng.3723
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260973