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[P3.065] Biomechanical drug testing by atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes

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PEŠL Martin PŘIBYL Jan BRAT Kristián ŠČUREK Martin SKLÁDAL Petr JELÍNKOVÁ Šárka KLIMOVIČ Šimon URBAN Tomáš ROTREKL Vladimír STÁREK Zdeněk

Rok publikování 2021
Druh Konferenční abstrakty
Citace
Popis Atomic force microscopy (AFM) combined with human cardiomyocytes allows the dynamic follow-up of contraction dynamics (e.g. beating rate, contraction, and relaxation time), simultaneously with other biomechanical properties. Today most drugs entering clinical usage has to be tested on arrhythmic adverse effects, nevertheless, the effect on cardiomyocyte contraction has been tested in very few substances, only related to cardiac pathologies. AFM-based biosensor allows in-vitro disease modeling but also enables monitoring the effect of cardiomyocyte-contraction affecting drugs. The ability of selected drugs to modulate contractility and spontaneous pacing was described in animal models. This work for the first time demonstrates that basic biomechanical parameters, such as the average value of contraction force and the beat rate represent valuable pharmacological indicators of different phenotypic effects on cells without genetic burden. The presented method is robust and has low computational requirements while keeping optimal spatial sensitivity (detection limit 200 pN, respectively 20 nm displacement). The heart stimulating activities of basic beta-adrenergic stimulators such as isoproterenol and adrenalin, but also drugs utilized in pneumology as ipratropium, or salbutamol were tested. Stimulating drugs, e.g. methylxanthines and caffeine, showed aberrant cardiomyocyte response, confirming arrhythmogenic potential, and showing force-related fluctuations. In the experiment, those could be diminished by beta-blockers as metoprolol. Spontaneous contraction irregularities quantification and related contractility changes allow precise scaling of potential negative effects adding new safety levels to clinically relevant drug testing. AFM combined with cardiomyocytes can serve as a robust screening platform for direct drug effects, especially contractility, which is hard to describe by other screening methods. Ref.: Pesl M, Pribyl J, Acimovic I, Vilotic A, Jelinkova S, Salykin A, Lacampagne A, Dvorak P, Meli AC, Skladal P, Rotrekl V. Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing. Biosens Bioelectron. 2016 Nov 15;85:751-757. doi: 10.1016/j.bios.2016.05.073 Caluori, G., J. Pribyl, M. Pesl, G. Nardone, P. Skladal and G. Forte (2018). "Advanced and rationalized atomic force microscopy analysis unveils specific properties of controlled cell mechanics. Front Physiol 9: 1121 Pribyl J, Pešl M, Caluori G, Acimovic I, Jelinkova S, Dvorak P, et al. Biomechanical Characterization of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Use of Atomic Force Microscopy. Methods Mol Biol. 2019;1886:343–53. Caluori, G., J. Pribyl, M. Pesl, S. Jelinkova, V. Rotrekl, P. Skladal and R. Raiteri Non-invasive electromechanical cell-based biosensors for improved investigation of 3D cardiac models. Biosens Bioelectron 2019, 124: 129-135.,10.1016/j.bios.2018.10.021 Jelinkova S, Vilotic A, Pribyl J, Aimond F, Salykin A, Acimovic I, et al. DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology. Front Bioeng Biotechnol 2020, DOI:10.3389/fbioe.2020.00535
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