Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits
Year: 2018
Type: article
Abstract: Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca 2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations.
Source: Stem Cell Reports
Authors: James G.W. Smith, Thomas Owen, Jamie R. Bhagwan, Diogo Mosqueira, Elizabeth Scott, Ingra Mannhardt, Asha Patel, Roberto Barriales-Villa, Lorenzo Monserrat, Arne Hansen, Thomas Eschenhagen, Sian E. Harding, Steve Marston, Chris Denning
Institutions: University of East Anglia, University of Nottingham, Norwich Research Park, Imperial College London, University Medical Center Hamburg-Eppendorf, German Centre for Cardiovascular Research, Universidade da Coruña, Complexo Hospitalario Universitario A Coruña, Servicio Gallego de Salud, Instituto de Investigación Biomédica de A Coruña
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,000
Funders: Deutsches Zentrum für Herz-Kreislaufforschung, British Heart Foundation, European Commission, National Centre for the Replacement, Refinement and Reduction of Animals in Research, Deutsche Forschungsgemeinschaft, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, BIRAX, Medical Research Council, Engineering and Physical Sciences Research Council, Instituto de Salud Carlos III, European Regional Development Fund, H2020 European Research Council
Awards: G1269907962, G1288996096, MICA: Development of Metrics and Quality Standards for Scale up of Human Pluripotent Stem Cells, G1640917251, G2196526216, BHF Imperial Cardiovascular Regenerative Medicine Centre, G3020690360, G3086692353, G3418652168, Mechanisms of arrhythmia generation from implanted stem cell-derived cardiomyocytes in infarcted hearts, G5113423502, Human cardiomyocytes from pluripotent stem cells to study β-adrenoceptor signalling (renewal), G710382481, G7162305877, Deep molecular phenotyping of myotonic dystrophy (DM1) hiPSC-cardiomyocytes to facilitate risk stratification and drug evaluation, G7531635858, G7670758531, G8127732077, Predicting anti-arrhythmic drug efficacy from the divergent molecular basis of RyR2 dysfunction in genetic arrhythmia syndromes. (Renewal), Coupling gene targeted reporters with fully automated compound library screening to mature hPSC-cardiomyocytes, RENEWAL: Molecular mechanisms by which mutations in myofibrillar proteins cause primary cardiomyopathies
OpenAlex ID: W2899259653