AG Hirt


Name: PD Dr. Dr. Marc Hirt
Clinic/Institute: Institute of Experimental Pharmacology and Toxicology
Email: m.hirt@uke.de
Phone: +49 (0) 40 7410 - 53180

Research Focus and Main research questions

Cardiac hypertrophy is the most important risk factor for the development of heart failure which is the leading cause of death in industrialized nations. We aim to decipher some of the molecular mechanisms of cardiac hypertrophy by a model of cardiac hypertrophy which we have developed over the past couple of years. It is based on engineered heart tissue (EHT), a 3-dimensional cell culture format for heart cells, which we subject to enhanced workload thus inducing phenotypical characteristics of cardiac disease.

The idea behind our cardiac hypertrophy model is the enhancement of afterload/workload (AE = afterload enhancement) of these small tissue strips by a simple mechanical metal brace. Most fascinating is that engineered heart tissues (EHTs) beat spontaneously. In contrast to simple cell cultures of cardiomyocytes EHTs provide therefore the optimal assay to assess the essential cardiac properties frequency and force, which can be analyzed automatically with technologies developed in our institute. “And it works!” The model of cardiac hypertrophy displays in vitro many aspects of cardiac hypertrophy/heart failure: Cardiomyocyte hypertrophy, fibrosis, metabolic changes towards glycolysis, characteristical changes in coding and noncoding RNAs and many more. Future directions: The next step we are working towards is the transition of this model of cardiac hypertrophy from rat heart cells to human heart cells. For this endeavor, we take advantage of the latest advances in stem cell technology.

The discovery of human induced pluripotent stem cells made it – in principal - possible to create all cell types in the human body including all types of human heart cells without ethical concerns or animal experiments. We have been able to create fluorescently labeled human multi-cell-type EHTs containing blue cardiomyocytes, green endothelial cells, orange smooth muscle cells and red fibroblasts. Lately, macrophages differentiated from pluripotent stem cells have been added to our portfolio of cells. EHTs in combination with a magnetics-based device that enables us to modulate stepwise increases in workload enable us to analyze the impact of timing and magnitude of afterload on human heart tissue to deeply investigate pathological cardiac hypertrophy (like in heart failure) and potentially even physiological cardiac hypertrophy (like in an athlete’s heart).

  • Methods
  • Methods

    Methods:

    • Generation of mono-cell-type human EHT with cardiomyocytes from human induced pluripotent stem cells
    • Generation of multi-cell-type human EHT (cardiomyocytes, endothelial cells, smooth muscle cells, fibroblasts, macrophages, all from human induced pluripotent stem cells)
    • Generation of rat EHT (engineered heart tissue, a 3-dimensional cell culture format for heart cells)
    • Automated contractility analysis of EHTs including contractile force, frequency, contraction and relaxation velocity, contraction and relaxation time, fractional shortening, arrhythmicity and many more
    • Analysis and modulation of non-coding RNAs (microRNAs, lncRNAs)
    • All standard molecular biology and microscopy techniques

  • Publications:

    Hypertrophic signaling compensates for contractile and metabolic consequences of DNA methyltransferase 3A loss in human cardiomyocytes. Madsen A, Krause J, Höppner G, Hirt MN, Tan WLW, Lim I, Hansen A, Nikolaev VO, Foo RSY, Eschenhagen T, Stenzig J. J Mol Cell Cardiol. 2021 May;154:115-123. doi: 10.1016/j.yjmcc.2021.02.002. Epub 2021 Feb 12. PMID: 33582159

    Assessment of Cardiotoxicity With Stem Cell-based Strategies. Stella Stoter AM, Hirt MN, Stenzig J, Weinberger F. Clin Ther. 2020 Oct;42(10):1892-1910. doi: 10.1016/j.clinthera.2020.08.012. Epub 2020 Sep 13. PMID: 32938533 Review.

    Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study. Funcke S, Werner TR, Hein M, Ulmer BM, Hansen A, Eschenhagen T, Hirt MN. Biomolecules. 2020 Sep 11;10(9):1309. doi: 10.3390/biom10091309. PMID: 32932811

    An Important Role for DNMT3A-Mediated DNA Methylation in Cardiomyocyte Metabolism and Contractility. Madsen A, Höppner G, Krause J, Hirt MN, Laufer SD, Schweizer M, Tan WLW, Mosqueira D, Anene-Nzelu CG, Lim I, Foo RSY, Eschenhagen T, Stenzig J. Circulation. 2020 Oct 20;142(16):1562-1578. doi: 10.1161/CIRCULATIONAHA.119.044444. Epub 2020 Sep 4. PMID: 32885664

    Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T. Eur Heart J. 2020 Sep 21;41(36):3462-3474. doi: 10.1093/eurheartj/ehaa519. PMID: 32657324

    Magnetic Adjustment of Afterload in Engineered Heart Tissues. Becker B, Rodriguez ML, Werner TR, Stenzig J, Eschenhagen T, Hirt MN. J Vis Exp. 2020 May 5;(159). doi: 10.3791/60811. PMID: 32449726

    Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction. Trembinski DJ, Bink DI, Theodorou K, Sommer J, Fischer A, van Bergen A, Kuo CC, Costa IG, Schürmann C, Leisegang MS, Brandes RP, Alekseeva T, Brill B, Wietelmann A, Johnson CN, Spring-Connell A, Kaulich M, Werfel S, Engelhardt S, Hirt MN, Yorgan K, Eschenhagen T, Kirchhof L, Hofmann P, Jaé N, Wittig I, Hamdani N, Bischof C, Krishnan J, Houtkooper RH, Dimmeler S, Boon RA. Nat Commun. 2020 Apr 27;11(1):2039. doi: 10.1038/s41467-020-15995-2. PMID: 32341350

    Phosphomimetic cardiac myosin-binding protein C partially rescues a cardiomyopathy phenotype in murine engineered heart tissue. Dutsch A, Wijnker PJM, Schlossarek S, Friedrich FW, Krämer E, Braren I, Hirt MN, Brenière-Letuffe D, Rhoden A, Mannhardt I, Eschenhagen T, Carrier L, Mearini G. Sci Rep. 2019 Dec 3;9(1):18152. doi: 10.1038/s41598-019-54665-2. PMID: 31796859.

    A magnetics-based approach for fine-tuning afterload in engineered heart tissues. Rodriguez ML, Werner TR, Becker B, Eschenhagen T, Hirt MN. ACS Biomater Sci Eng. 2019 Jul 8;5(7):3663-3675. doi: 10.1021/acsbiomaterials.8b01568. Epub 2019 Jun 11. PMID: 31637285

    Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis. Kenneweg F, Bang C, Xiao K, Boulanger CM, Loyer X, Mazlan S, Schroen B, Hermans-Beijnsberger S, Foinquinos A, Hirt MN, Eschenhagen T, Funcke S, Stojanovic S, Genschel C, Schimmel K, Just A, Pfanne A, Scherf K, Dehmel S, Raemon-Buettner SM, Fiedler J, Thum T. Mol Ther Nucleic Acids. 2019 Dec 6;18:363-374. doi: 10.1016/j.omtn.2019.09.003. Epub 2019 Sep 13. PMID: 31634682

    Blockade of miR-140-3p prevents functional deterioration in afterload-enhanced engineered heart tissue. Werner TR, Kunze AC, Stenzig J, Eschenhagen T, Hirt MN. Sci Rep. 2019 Aug 7;9(1):11494. doi: 10.1038/s41598-019-46818-0. PMID: 31391475

    Toward Second-Generation Cardiomyogenic and Anti-cardiofibrotic 1,4-Dihydropyridine-Class TGFβ Inhibitors. Längle D, Werner TR, Wesseler F, Reckzeh E, Schaumann N, Drowley L, Polla M, Plowright AT, Hirt MN, Eschenhagen T, Schade D. ChemMedChem. 2019 Apr 17;14(8):810-822. doi: 10.1002/cmdc.201900036. Epub 2019 Feb 28. PMID: 30768867

    S100A4 as a Target of the E3-Ligase Asb2β and Its Effect on Engineered Heart Tissue. Braumann S, Thottakara T, Stücker S, Reischmann-Düsener S, Krämer E, Groß J, Hirt MN, Doroudgar S, Carrier L, Friedrich FW. Front Physiol. 2018 Sep 19;9:1292. doi: 10.3389/fphys.2018.01292. eCollection 2018. PMID: 30283351

    Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. Stenzig J, Schneeberger Y, Löser A, Peters BS, Schaefer A, Zhao RR, Ng SL, Höppner G, Geertz B, Hirt MN, Tan W, Wong E, Reichenspurner H, Foo RS, Eschenhagen T. J Mol Cell Cardiol. 2018 Jul;120:53-63. doi: 10.1016/j.yjmcc.2018. 05.012. Epub 2018 May 21. PMID: 29792884

    Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density. Lemoine MD, Mannhardt I, Breckwoldt K, Prondzynski M, Flenner F, Ulmer B, Hirt MN, Neuber C, Horváth A, Kloth B, Reichenspurner H, Willems S, Hansen A, Eschenhagen T, Christ T. Sci Rep. 2017 Jul 14;7(1):5464. doi: 10.1038/s41598-017-05600-w. PMID: 28710467

    Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation. Barallobre-Barreiro J, Gupta SK, Zoccarato A, Kitazume-Taneike R, Fava M, Yin X, Werner T, Hirt MN, Zampetaki A, Viviano A, Chong M, Bern M, Kourliouros A, Domenech N, Willeit P, Shah AM, Jahangiri M, Schaefer L, Fischer JW, Iozzo RV, Viner R, Thum T, Heineke J, Kichler A, Otsu K, Mayr M. Circulation. 2016 Sep 13;134(11):817-32. doi: 10.1161/CIRCULATIONAHA.115.016423. Epub 2016 Aug 24. PMID: 27559042

    Human Engineered Heart Tissue: Analysis of Contractile Force. Mannhardt I, Breckwoldt K, Letuffe-Brenière D, Schaaf S, Schulz H, Neuber C, Benzin A, Werner T, Eder A, Schulze T, Klampe B, Christ T, Hirt MN, Huebner N, Moretti A, Eschenhagen T, Hansen A. Stem Cell Reports. 2016 Jul 12;7(1):29-42. doi: 10.1016/j.stemcr.2016.04.011. Epub 2016 May 19. PMID: 27211213

    Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia. Schäfer M, Oeing CU, Rohm M, Baysal-Temel E, Lehmann LH, Bauer R, Volz HC, Boutros M, Sohn D, Sticht C, Gretz N, Eichelbaum K, Werner T, Hirt MN, Eschenhagen T, Müller-Decker K, Strobel O, Hackert T, Krijgsveld J, Katus HA, Berriel Diaz M, Backs J, Herzig S. Mol Metab. 2015 Nov 26;5(2):67-78. doi: 10.1016/j.molmet.2015.11.004. eCollection 2016 Feb. PMID: 26909315

    Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. Jacob F, Yonis AY, Cuello F, Luther P, Schulze T, Eder A, Streichert T, Mannhardt I, Hirt MN, Schaaf S, Stenzig J, Force T, Eschenhagen T, Hansen A. PLoS One. 2016 Feb 3;11(2):e0145937. doi: 10.1371/journal.pone.0145937. eCollection 2016. PMID: 26840448

    Spontaneous Formation of Extensive Vessel-Like Structures in Murine Engineered Heart Tissue. Stoehr A*, Hirt MN* (*equal contribution), Hansen A, Seiffert M, Conradi L, Uebeler J, Limbourg FP, Eschenhagen T. Tissue Eng Part A. 2016 Feb;22(3-4):326-35. doi: 10.1089/ten.TEA.2015. 0242. PMID: 26763667

    DNA methylation in an engineered heart tissue model of cardiac hypertrophy: common signatures and effects of DNA methylation inhibitors. Stenzig J*, Hirt MN (*equal contribution), Löser A, Bartholdt LM, Hensel JT, Werner TR, Riemenschneider M, Indenbirken D, Guenther T, Müller C, Hübner N, Stoll M, Eschenhagen T. Basic Res Cardiol. 2016 Jan;111(1):9. doi: 10.1007/s00395-015-0528-z. Epub 2015 Dec 17. PMID: 26680771

    General practitioners' adherence to chronic heart failure guidelines regarding medication: the GP-HF study.Hirt MN, Muttardi A, Helms TM, van den Bussche H, Eschenhagen T. Clin Res Cardiol. 2016 May;105(5):441-50. doi: 10.1007/s00392-015-0939-8. Epub 2015 Nov 9. PMID: 26552905

    Deciphering the microRNA signature of pathological cardiac hypertrophy by engineered heart tissue- and sequencing-technology.Hirt MN, Werner T, Indenbirken D, Alawi M, Demin P, Kunze AC, Stenzig J, Starbatty J, Hansen A, Fiedler J, Thum T, Eschenhagen T. J Mol Cell Cardiol. 2015 Apr;81:1-9. doi: 10.1016/j.yjmcc.2015.01.008. Epub 2015 Jan 26. PMID: 25633833

    Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation.Hirt MN, Boeddinghaus J, Mitchell A, Schaaf S, Börnchen C, Müller C, Schulz H, Hubner N, Stenzig J, Stoehr A, Neuber C, Eder A, Luther PK, Hansen A, Eschenhagen T. J Mol Cell Cardiol. 2014 Sep;74:151-61. doi: 10.1016/j.yjmcc.2014.05.009. Epub 2014 May 19. PMID: 24852842

    Automated analysis of contractile force and Ca2+ transients in engineered heart tissue. Stoehr A, Neuber C, Baldauf C, Vollert I, Friedrich FW, Flenner F, Carrier L, Eder A, Schaaf S, Hirt MN, Aksehirlioglu B, Tong CW, Moretti A, Eschenhagen T, Hansen A. Am J Physiol Heart Circ Physiol. 2014 May;306(9):H1353-63. doi: 10.1152/ajpheart.00705.2013. Epub 2014 Feb 28. PMID: 24585781

    Cardiac tissue engineering: state of the art.Hirt MN, Hansen A, Eschenhagen T. Circ Res. 2014 Jan 17;114(2):354-67. doi: 10.1161/CIRCRESAHA.114.300522. Review. PMID: 24436431

    Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice. Stöhr A, Friedrich FW, Flenner F, Geertz B, Eder A, Schaaf S, Hirt MN, Uebeler J, Schlossarek S, Carrier L, Hansen A, Eschenhagen T. J Mol Cell Cardiol. 2013 Oct;63:189-98. doi: 10.1016/j.yjmcc.2013.07.011. Epub 2013 Jul 26. PMID: 23896226

    Increased afterload induces pathological cardiac hypertrophy: a new in vitro model.Hirt MN, Sörensen NA, Bartholdt LM, Boeddinghaus J, Schaaf S, Eder A, Vollert I, Stöhr A, Schulze T, Witten A, Stoll M, Hansen A, Eschenhagen T. Basic Res Cardiol. 2012 Nov;107(6):307. doi: 10.1007/s00395-012-0307-z. Epub 2012 Oct 26. PMID: 23099820

    Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. Schaaf S, Shibamiya A, Mewe M, Eder A, Stöhr A, Hirt MN, Rau T, Zimmermann WH, Conradi L, Eschenhagen T, Hansen A. PLoS One. 2011;6(10):e26397. doi: 10.1371/journal.pone.0026397. Epub 2011 Oct 20. PMID: 22028871

  • Recent Funding:

    Grants from the German Israeli Foundation (GIF) and from the TRAIN-HEART consortium, funded by the European Commission.

Research Team

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