Cardiomyocyte contraction and relaxation are important parameters of cardiac function altered in many heart pathologies. Biosensing of these parameters represents an important tool in drug development and disease modeling. Human embryonic stem cells and especially patient specific induced pluripotent stem cell-derived cardiomyocytes are well established as cardiac disease model.. Here, a live stem cell derived embryoid body (EB) based cardiac cell syncytium served as a biorecognition element coupled to the microcantilever probe from atomic force microscope thus providing reliable micromechanical cellular biosensor suitable for whole-day testing. The biosensor was optimized regarding the type of cantilever, temperature and exchange of media; in combination with standardized protocol, it allowed testing of compounds and conditions affecting the biomechanical properties of EB. The studied effectors included calcium , drugs modulating the catecholaminergic fight-or-flight stress response such as the beta-adrenergic blocker metoprolol and the beta-adrenergic agonist isoproterenol. Arrhythmogenic effects were studied using caffeine. Furthermore, with EBs originating from patient's stem cells, this biosensor can help to characterize heart diseases such as dystrophies.
Duchenne muscular dystrophy (DMD) is associated with progressive dilated cardiomyopathy eventually leading to heart failure as the main cause of death in DMD patients. A human cardiomyocyte (CM) model was developed from several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and hESC line with deletion of DMD gene generated by CRISPR/Cas9 technology. DMD hPSC were differentiated into CMs. DMD mutation-carrying cells are less prone to differentiate into CMs. DMD CMs further demonstrate an enhanced cell death rate. Ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (DHPR overexpression). DMD-CMs exhibited mishandling of calcium demonstrated by increased time of calcium release. Further mechanical impairment (hypocontractility), bradycardia, increased beat rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors' expression was found in DMD-CMs (LTCC L-type calcium channel, cTnT-cardiac troponin T, Kir2.1-potassium channel).
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