Abstract
We have developed an engineered heart tissue (EHT) system that uses laser-cut sheets of decellularized myocardium as scaffolds. This material enables formation of thin muscle strips whose biomechanical characteristics are easily measured and manipulated. To create EHTs, sections of porcine myocardium were laser-cut into ribbon-like shapes, decellularized, and mounted in specialized clips for seeding and culture. Scaffolds were first tested by seeding with neonatal rat ventricular myocytes. EHTs beat synchronously by day five and exhibited robust length-dependent activation by day 21. Fiber orientation within the scaffold affected peak twitch stress, demonstrating its ability to guide cells toward physiologic contractile anisotropy. Scaffold anisotropy also made it possible to probe cellular responses to stretch as a function of fiber angle. Stretch that was aligned with the fiber direction increased expression of brain natriuretic peptide, but off-axis stretches (causing fiber shear) did not. The method also produced robust EHTs from cardiomyocytes derived from human embryonic stem cells and induced pluripotent stem cells (hiPSC). hiPSC-EHTs achieved maximum peak stress of 6.5 mN/mm2 and twitch kinetics approaching reported values from adult human trabeculae. We conclude that laser-cut EHTs are a viable platform for novel mechanotransduction experiments and characterizing the biomechanical function of patient-derived cardiomyoctyes.
Highlights
Abnormal growth and remodeling of the myocardium are central features in many heart disorders, including hypertensive heart disease, myocardial infarction, and inherited cardiomyopathies[1]
These studies and others highlight the clear potential of decellularized myocardium to produce cardiac tissues with realistic anisotropy, but until now this technology has not been adapted for biomechanical experiments, which require the ability to both measure and manipulate mechanical loading of engineered heart tissue (EHT) in precise ways
EHT morphology and remodeling were followed over time using Optical Coherence Tomography (OCT) imaging (Fig. 3a)
Summary
Abnormal growth and remodeling of the myocardium are central features in many heart disorders, including hypertensive heart disease, myocardial infarction, and inherited cardiomyopathies[1] Such phenomena are challenging to study because of the many different factors that can perturb cardiac tissue homeostasis in vivo. Thick slices of decellularized myocardium have been immobilized on cover glass and seeded with NRVMs to produce tissue sheets with anisotropic action potential conduction[14] These studies and others highlight the clear potential of decellularized myocardium to produce cardiac tissues with realistic anisotropy, but until now this technology has not been adapted for biomechanical experiments, which require the ability to both measure and manipulate mechanical loading of EHTs in precise ways. The clipping system enables precise application of novel mechanical perturbations (such as shear strain) and makes measurements of mechanical function rapid and reliable
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