Evidence for synergy between sarcomeres and fibroblasts in an in vitro model of myocardial reverse remodeling. (September 2021)

• Record Type: Journal Article
• Authors: Shen, Shi; Sewanan, Lorenzo R.; Campbell, Stuart G.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 158(2021)
• Page Start: 11
• Page End: 25
• Publication Date: 2021-09
• Subjects: Myocardial remodeling -- Sarcomere -- Mechanotransduction -- Engineered heart tissue; α-SMA alpha-smooth muscle actin -- cTnT cardiac troponin T -- DC drug control -- DCM dilated cardiomyopathy -- DIRR double-inhibited reverse remodeling -- DT destination therapy -- ECM extracellular matrix -- EHT engineered heart tissue -- FIRR fibroblast-inhibited reverse remodeling -- Ctrl Control group -- HCF human cardiac fibroblast -- HF heart failure -- hiPSC-CMs human induced pluripotent stem cell-derived cardiomyocytes -- IHC immunohistochemistry -- LVAD left ventricular assist device -- LVEF left ventricular ejection fraction -- MMP matrix metalloproteinase -- NRVMs neonatal rat ventricular myocytes -- NRCFs neonatal rat cardiac fibroblasts -- OM Omecamtiv Mecarbil -- OCT optical coherence tomography -- PF peak fore -- REMATCH randomized evaluation of mechanical assistance for the treatment of congestive heart failure -- RR reverse remodeling -- RT50 time to 50% relaxation from the peak -- SIRR sarcomere-inhibited reverse remodeling -- TGF-β Transforming growth factor- β -- TIMP tissue inhibitors of metalloproteinase -- TTP time to peak; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.05.005
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: We have created a novel in-vitro platform to study reverse remodeling of engineered heart tissue (EHT) after mechanical unloading. EHTs were created by seeding decellularized porcine myocardial sections with a mixture of primary neonatal rat ventricular myocytes and cardiac fibroblasts. Each end of the ribbon-like constructs was fixed to a plastic clip, allowing the tissues to be statically stretched or slackened. Inelastic deformation was introduced by stretching tissues by 20% of their original length. EHTs were subsequently unloaded by returning tissues to their original, shorter length. Mechanical characterization of EHTs immediately after unloading and at subsequent time points confirmed the presence of a reverse-remodeling process, through which stress-free tissue length was increased after chronic stretch but gradually decreased back to its original value within 9 days. When a cardiac myosin inhibitor was applied to tissues after unloading, EHTs failed to completely recover their passive and active mechanical properties, suggesting a role for actomyosin contraction in reverse remodeling. Selectively inhibiting cardiomyocyte contraction or fibroblast activity after mechanical unloading showed that contractile activity of both cell types was required to achieve full remodeling. Similar tests with EHTs formed from human induced pluripotent stem cell-derived cardiomyocytes also showed reverse remodeling that was enhanced when treated with omecamtiv mecarbil, a myosin activator. These experiments suggest essential roles for active sarcomeric contraction and fibroblast activity in reverse remodeling of myocardium after mechanical unloading. Our findings provide a mechanistic rationale for designing potential therapies to encourage reverse remodeling in patient hearts. Graphical abstract: Unlabelled Image Highlights: Reverse remodeling is a phenomenon seen in some failing hearts after unloading. Engineered heart tissues exhibit reverse remodeling-like behavior after unloading. The cardiac myosin inhibitor mavacamten blunted in vitro reverse remodeling. An inhibitor of fibroblast activation also prevented in vitro reverse remodeling. Myocardial reverse remodeling apparently requires activity of sarcomeres and fibroblasts.