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Research Group Christ
Electrophysiology of human induced pluripotent stem cell-derived cardiomyocytes
(hiPSC-CM)
Aim
We aim to use hiPSC-CM as model to study electrophysiology of the human heart under physiological and pathophysiological conditions
Scope of Research
Action potentials • ion currents• patch clamp • contractility
Research Projects
The development of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) is expected to become a step forward to increase the translational power of cardiovascular research. Importantly they should allow to study genetic effects on an electrophysiological background close to the human situation. Obviously, the value of hiPSC-CM as a model will depend on how closely hiPSC-CM resembles adult cardiomyocytes. We are therefore interested in the contribution of individual ion currents and their regulation by receptors to electrical activity in hiPSC-CM vs. the adult human ventricular and atrial tissue.
1. Impact of genes in the PITX2 locus on the electrophysiology of human atrial induced pluripotent stem cell-derived cardiomyocytes (together with Prof. Dr. Thomas Eschenhagen & Prof. Dr. Monika Stoll, Muenster)
Genome wide association studies (GWAS) have identified several gene variants associated with AF. The strongest association was found with single nucleotide polymorphisms (SNP) in a gene locus near the PITX2 gene. In human atria of patients with SNPs close to PITX2 PITX2-exprsseion is not changed. In contrast, a gene close to PITX2, the ENPEP-AS1 showed an association with AF. This finding opens the possibility that changes in genes close to PITX2 but not PITX2-expression associate with AF. Gene editing of the ENPEP-AS1 in WT and PITX2-KO atrial hiPSC-CM cell line should allow to answer the question.
2. Contribution of SERCA2, RyR2, NCX1 and PMCA to excitation-contraction coupling in human cardiomyocytes – tackling an old question with modern technologies (together with Prof. Dr. Thomas Eschenhagen)
Several well-performed studies indicate that neither pharmacological nor genetic inhibition of SERCA2 or NCX1 strongly affect force of contraction. Given the limitations of pharmacological interventions, more work with definite methods is needed to solve the apparent conundrum. The project uses advanced methods to genetically manipulate and study cardiomyocyte excitation-contraction coupling under controlled conditions.
3. Effects of sex hormones on electrophysiological properties of human induced stem cell-derived atrial cardiomyocytes (together with Dr. Djemail Ismaili & Prof. Dr. Thomas Eschenhagen)
The aim of this proposed project is to use atrial EHT (aEHT) to investigate whether sex hormones play a relevant role in regulation of the resting membrane potential. For this purpose, we will measure acute and chronic effects of estrogen and testosterone in EHT from atrial hiPSC-CM from females and males. We will compare gene expression and action potentials parameters. Depending on results, selected on currents will be measured.
4. EHT as a model to study exercise-induced arrhythmias in HCM (within the SMASH-HCM consortium)
Work is done within the EU-founded consortium SMASH-HCM “Stratification, Management and Guidance of Hypertrophic Cardiomyopathy Patients using Hybrid Digital Twin Solutions”. Specifically, we use EHT from patients with HCM and from healthy probands to mimic exercise-associated changes of homeostasis like temperature, pH, extracellular potassium and norepinephrine. Results are used for computer modeling of electrical activity of human heart.
Key Techniques
- AP recording in intact cardiac tissues with sharp microelectrodes,
- Patch clamp in isolated cardiomyocytes
- Patch clamp in isolated cardiomyocytes,
Force measurements in cardiac tissues
Group Members
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Publications
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Human Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue as a Sensitive Test System for QT Prolongation and Arrhythmic Triggers.
Lemoine MD, Krause T, Koivumäki JT, Prondzynski M, Schulze ML, Girdauskas E, Willems S, Hansen A, Eschenhagen T, Christ T
Circ Arrhythm Electrophysiol. 2018 Jul;11(7):e006035. doi: 10.1161/CIRCEP.117.006035 -
Disease modeling of a mutation in α-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy
Prondzynski M, Lemoine MD, Zech AT, Horváth A, Di Mauro V, Koivumäki JT, Kresin N, Busch J, Krause T, Krämer E, Schlossarek S, Spohn M, Friedrich FW, Münch J, Laufer SD, Redwood C, Volk AE, Hansen A, Mearini G, Catalucci D, Meyer C, Christ T, Patten M, Eschenhagen T, Carrier L
EMBO Mol Med. 2019 Dec;11(12):e11115. doi: 10.15252/emmm.201911115. -
Atrial-like Engineered Heart Tissue: An In Vitro Model of the Human Atrium.
Lemme M, Ulmer BM, Lemoine MD, Zech ATL, Flenner F, Ravens U, Reichenspurner H, Rol-Garcia M, Smith G, Hansen A, Christ T, Eschenhagen T
Stem Cell Reports. 2018 Dec 11;11(6):1378-1390. doi: 10.1016/j.stemcr.2018.10.008 -
PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation
Schulz C, Lemoine MD, Mearini G, Koivumäki J, Sani J, Schwedhelm E, Kirchhof P, Ghalawinji A, Stoll M, Hansen A, Eschenhagen T, Christ T
Circ Arrhythm Electrophysiol. 2023 Mar;16(3):e011602. doi: 10.1161/CIRCEP.122.011602 -
Human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium
Sönmez MI, Goldack S, Nurkkala E, Schulz C, Klampe B, Schulze T, Hansen A, Eschenhagen T, Koivumäki J, Christ T
Europace. 2024 Jun 3;26(6):euae140. doi: 10.1093/europace/euae140.
Grants/Awards
- Impact of genes in the PITX2 locus on the electrophysiology of human atrial induced pluripotent stem cell-derived cardiomyocytes, DFG (together with Prof. Dr. Thomas Echenhagen & Prof. Dr. Monika Stoll)
- Contribution of SERCA2, RyR2, NCX1 and PMCA to excitation-contraction coupling in human cardiomyocytes – tackling an old question with modern technologies, DFG (together with Thomas Eschenhagen)
- SMASH: Stratification, Management, and Guidance of Hypertrophic Cardiomyopathy Patients using Hybrid Digital Twin Solutions; EU (consortium)
Most important collaboration partners
- Prof. Dr. Thomas Eschenhagen, UKE Hamburg
- Prof. Dr. Arne Hansen, UKE Hamburg
- Prof. Dr. Evaldas Girdauskas, UKE Hamburg
- Prof. Dr. Jussi Koivumäki, Tampere, Finland
- Prof. Dr. Monika Stoll, Münster; Germany