Marta Lemme

Nanion (Germany)

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Arne Hansen

German Centre for Cardiovascular Research

Thomas Eschenhagen

German Centre for Cardiovascular Research

Michael George

Nanion (Germany)

Niels Fertig

Nanion (Germany)

Dorit Schuster

University Hospital Schleswig-Holstein

Ole Ammerpohl

Universität Ulm

Thomas Pickardt

German Centre for Cardiovascular Research

Elena Dragicevic

Nanion (Germany)

Bärbel Ulmer

Universität Hamburg

Kerstin Runde

University Hospital Schleswig-Holstein

Cooperative Institutions

German Centre for Cardiovascular Research

University Medical Center Hamburg-Eppendorf

Universität Hamburg

Nanion (Germany)

University Hospital Schleswig-Holstein

University of Lübeck

Kiel University

Institute of Experimental Pharmacology and Toxicology of the Slovak Academy of Sciences

Cardiovascular Research Center

Ludwig-Maximilians-Universität München

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Intermittent Optogenetic Tachypacing of Atrial Engineered Heart Tissue Induces Only Limited Electrical Remodelling

Journal of Cardiovascular Pharmacology (2020)

Marc D. Lemoine Marta Lemme Bärbel Ulmer Ingke Braren Susanne Krasemann

Abstract: Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) provide a novel human source to model cardiovascular diseases. Here, we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling. After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 seconds twice a minute over 3 weeks and compared with transduced spontaneously beating isogenic aEHTs (1.95 ± 0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138 ± 15 vs. 87 ± 11 V/s, n = 15–13/3; P = 0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0 ± 1.8 vs. 68.0 ± 1.9 mV; P = 0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07 ± 0.01 vs. 0.03 ± 0.004 seconds, n = 15–13/3; P = 0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 [Kir2.2, inward rectifier (I K1 ); 69 ± 7 vs. 44 ± 4, P = 0.014] and NPPB (NT-proBNP; 39,690 ± 4834 vs. 23,671 ± 3691; P = 0.024). Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation may clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation.

Beat (acoustics)

10.1097/fjc.0000000000000951

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Citations (12)

Integration of mechanical conditioning into a high throughput contractility assay for cardiac safety assessment

Journal of Pharmacological and Toxicological Methods (2020)

Matthias Goßmann Peter Linder Ulrich Thomas Krisztina Juhász Marta Lemme

Contractility

hERG

10.1016/j.vascn.2020.106892

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Citations (12)

Hybrid Cell Analysis System to Assess Structural and Contractile Changes of Human iPSC-Derived Cardiomyocytes for Preclinical Cardiac Risk Evaluation

Journal of Visualized Experiments (2022)

Bettina Lickiss Matthias Goßmann Peter Linder Ulrich Thomas Elena Dragicevic

Cardiac contractility assessment is of immense importance for the development of new therapeutics and their safe transition into clinical stages. While human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold promise to serve as a human-relevant model in preclinical phases of drug discovery and safety pharmacology, their maturity is still controversial in the scientific community and under constant development. We present a hybrid contractility and impedance/extracellular field potential (EFP) technology, adding significant pro-maturation features to an industry-standard 96-well platform. The impedance/EFP system monitors cellular functionality in real-time. Besides the beat rate of contractile cells, the electrical impedance spectroscopy readouts detect compound-induced morphological changes like cell density and integrity of the cellular monolayer. In the other component of the hybrid cell analysis system, the cells are cultured on bio-compliant membranes that mimic the mechanical environment of real heart tissue. This physiological environment supports the maturation of hiPSC-CMs in vitro, leading to more adult-like contractile responses including positive inotropic effects after treatment with isoproterenol, S-Bay K8644, or omecamtiv mecarbil. Parameters such as the amplitude of contraction force (mN/mm2) and beat duration also reveal downstream effects of compounds with influence on electrophysiological properties and calcium handling. The hybrid system provides the ideal tool for holistic cell analysis, allowing preclinical cardiac risk assessment beyond the current perspectives of human-relevant cell-based assays.

Contractility

Safety pharmacology

10.3791/64283-v

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Citations (2)

Mechanical stimulation in a 2D high-throughput contractility system induces functional changes in human induced pluripotent stem cell-derived cardiomyocytes

Journal of Pharmacological and Toxicological Methods (2021)

Marta Lemme Peter Linder Ulrich Thomas Elena Dragicevic Michael George

Contractility

10.1016/j.vascn.2021.107022

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Citations (0)

P1587Retinoic acid-treated HIPSC-CM: a suitable model for human atrium?

EP Europace (2017)

Marta Lemme Bärbel Ulmer ATL Zech Torsten Christ Thomas Eschenhagen

Atrium (architecture)

10.1093/ehjci/eux158.213

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Human Engineered Heart Tissue Patches Remuscularize the Injured Heart in a Dose-Dependent Manner

Circulation (2021)

Eva Querdel Marina Reinsch Liesa Castro Deniz Köse Andrea Bähr

Human engineered heart tissue (EHT) transplantation represents a potential regenerative strategy for patients with heart failure and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices, and determination of the effective dose.Cardiomyocytes were differentiated from 3 different human induced pluripotent stem cell lines including one reprogrammed under good manufacturing practice conditions. Protocols for human induced pluripotent stem cell expansion, cardiomyocyte differentiation, and EHT generation were adapted to substances available in good manufacturing practice quality. EHT geometry was modified to generate patches suitable for transplantation in a small-animal model and perspectively humans. Repair efficacy was evaluated at 3 doses in a cryo-injury guinea pig model. Human-scale patches were epicardially transplanted onto healthy hearts in pigs to assess technical feasibility.We created mesh-structured tissue patches for transplantation in guinea pigs (1.5×2.5 cm, 9-15×106 cardiomyocytes) and pigs (5×7 cm, 450×106 cardiomyocytes). EHT patches coherently beat in culture and developed high force (mean 4.6 mN). Cardiomyocytes matured, aligned along the force lines, and demonstrated advanced sarcomeric structure and action potential characteristics closely resembling human ventricular tissue. EHT patches containing ≈4.5, 8.5, 12×106, or no cells were transplanted 7 days after cryo-injury (n=18-19 per group). EHT transplantation resulted in a dose-dependent remuscularization (graft size: 0%-12% of the scar). Only high-dose patches improved left ventricular function (+8% absolute, +24% relative increase). The grafts showed time-dependent cardiomyocyte proliferation. Although standard EHT patches did not withstand transplantation in pigs, the human-scale patch enabled successful patch transplantation.EHT patch transplantation resulted in a partial remuscularization of the injured heart and improved left ventricular function in a dose-dependent manner in a guinea pig injury model. Human-scale patches were successfully transplanted in pigs in a proof-of-principle study.

Human heart

10.1161/circulationaha.120.047904

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Citations (102)

A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation

Integrative Biology (2018)

Paola Occhetta Giuseppe Isu Marta Lemme Chiara Conficconi Philipp Oertle

Our 3D-scar-on-a-chip model resembles fibroblast proliferation and activation, extracellular matrix deposition and stiffening upon application of only cyclic mechanical stretching.

Stiffening

Matrix (chemical analysis)

Deposition

Matrix model

10.1039/c7ib00199a

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Citations (36)

Human-Engineered Atrial Tissue for Studying Atrial Fibrillation

Methods in molecular biology (2022)

Julia Krause Marta Lemme Ingra Mannhardt Alexandra Eder Bärbel Ulmer

Atrium (architecture)

Contractility

10.1007/978-1-0716-2261-2_11

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Citations (3)

Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue

Journal of Molecular and Cellular Cardiology (2021)

Justus Stenzig Marc D. Lemoine Aaltje Maria Stella Stoter Kinga M. Wrona Marta Lemme

BackgroundOne third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT.MethodsCardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously.ResultsAsymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca2+-sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca2+-signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5–0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower.ConclusionsThis model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT.

Afterload

10.1016/j.yjmcc.2021.10.001

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Citations (1)