YAP1 reactivation in cardiomyocytes following ECM remodelling contributes to the development of contractile force and sarcomere maturation
Year: 2025
Type: article
Abstract: Cardiac diseases are fueled by extracellular matrix (ECM) remodelling. Together with the altered ECM chemical composition, the mechanical turmoil associated with ECM maladaptive remodelling in the pathological heart drives the shuttling of Yes Associated Protein 1 (YAP1) into cardiomyocyte (CM) nuclei that results either in cell cycle re-entry or cardiomyocyte hypertrophy. The mechanism of YAP1 reactivation and factors driving qualitatively different cellular outcomes is not well understood. Here we employed mechanical actuation as a proxy reproducing ECM remodelling in vitro to trigger YAP1 nuclear shuttling in contractile cardiomyocytes derived from human embryonic and induced pluripotent stem cells (hPSCs). By using hPSC lines in which YAP1 expression has been genetically depleted, super-resolution microscopy and electrophysiological measurements, we show that ECM-triggered nuclear presence of endogenous YAP1 contributes to cardiomyocyte maturation, participates in the formation and alignment of myofibrils, as well as in the maturation of their electrophysiological properties and calcium dynamics. We eventually exploit engineered heart tissues (EHTs) to demonstrate that the net effect of YAP1 deficiency in cardiomyocytes is the inability to respond to physiological stimuli by compensatory growth that results in reduced force development. These results suggest that the re-activation of endogenous YAP1 following ECM maladaptive remodelling promotes cardiomyocyte contractility by restructuring the sarcomere apparatus and the maturation of electrophysiological properties via transcriptionally dependent and independent mechanisms.
Source: Cell Death Discovery
Institutions: Masaryk University, International Clinical Research Center, St. Anne's University Hospital Brno, St. Anne's University Hospital Brno, King's College London, Imperial College London, University of Bern, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Theoretical and Applied Mechanics, University of Milan, University of Milano-Bicocca, RWTH Aachen University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: UK Research and Innovation, British Heart Foundation, King's College London, European Commission, Deutsche Forschungsgemeinschaft, Ministerstvo Školství, Mládeže a Tělovýchovy, HORIZON EUROPE Framework Programme, Engineering and Physical Sciences Research Council, Menzies Centre for Australian Studies, King's College London, University of London, European Regional Development Fund
Awards: G1016895160, G1059663884, G1067330246, Research Excellence (round 3), G176604203, G2039240949, G2199443702, National Infrastructure for Biological and Medical Imaging, G2270135567, Investigating the role of YAP in protecting ventricular cardiomyocyte nuclear integrity against mechanical stress, G2441402196, G2783698034, G291036901, G310317919, Multiscale quantum bio-imaging and spectroscopy, G3316040122, G3490171961, G3622461675, G3732336168, G495789545, G5124248554, G5641063287, G5916014575, G6018226045, G6236323351, G6475829272, G7363506711, G879140356, The mechanical regulation of microRNA epitranscriptomics in heart failure, GRK 2415: Mechanobiology in Epithelial 3D Tissue Constructs, G8961372790
OpenAlex ID: W4416087867