A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

“…iPSC-derived VSMCs have also been utilized for patient-tailored drug discovery efforts; for example, one group recently performed a small molecule screen in MFS VSMCs and showed that GSK3β (glycogen synthase kinase-3 beta) inhibition resulted in partial phenotypic rescue. 97 With CRISPR/ Cas9 genome-editing technology, one can now correct the disease-associated mutation and thereby generate isogenic controls to minimize the impact of divergent genetic backgrounds on phenotype. Additionally, researchers are no longer restricted to modeling patient-identified mutations but can interrogate the phenotypic impact of nearly any genetic disruption.…”

Understanding genomic medicine for thoracic aortic disease through the lens of induced pluripotent stem cells

“…Individual proteins such as elastin and collagen deposition have been evaluated using human VSMCs ( 38 , 39 ). Secretome forms a huge part of VSMC matrix modulatory phenotypic responses and number of studies have explored this using ELISA-based MMP assays and zymography for MMPs and tissue inhibitors of metalloproteinases ( 40 , 41 ). The potential of quantifying nascent ECM secretion through BONCAT mass spectroscopy has been shown with other disease models but could be also applied to TAD ( 42 ).…”

“…The ability of these protocols to produce vascular bed or niche-specific cells is important because some vascular diseases often show region-specific susceptibility to aneurysm formation e.g., aortic root aneurysms in LDS. Our own studies on MFS have provided huge insights into how patient iPSC-derived VSMCs are capable of clearly reflecting disease severity in vitro while uncovering the differential response to drugs between patients ( 22 , 40 ) and hence are an invaluable platform for the development of personalised, tailored therapeutics.…”

“…Coupling CRISPR gene editing technology with iPSCs has allowed for significant enhancement of aortic disease models such as syndromic aortopathies ( 22 , 40 , 87 , 88 ) and aortopathy genetic variants ( 61 , 139 ). Correction of a FBN1 mutation demonstrated rescue of in vitro MFS disease phenotype ( 87 ).…”

“…For example, pharmacological inhibition of PDGF signalling in iPSC-derived cardiomyocytes in LMNA-related dilated cardiomyopathy, ameliorated the arrhythmic phenotypes ( 189 ). Further, even disease severity modelling and prediction both have been successful in (a) Brugada syndrome where cardiomyocytes are affected by arrhythmogenesis of different severity ( 190 ) (b) Marfan syndrome where proteolytic degradation by vascular smooth muscle cells was used to scored disease severity and response to drugs inhibiting Gsk3β activity to restore proliferation, curtail apoptosis and MMP secretion ( 40 ) and (c) Alport syndrome where kidney organoids modelled severity based on extent of accumulation of Collagens and a marked reduction in the same was demonstrated by the use of chemical chaperones ( 191 ). Atherosclerotic plaque stability was demonstrated by KLF4 attenuation by ANGPTL4 treatment of iPSC-derived vascular smooth muscle cells and in mouse models ( 192 ).…”