AG Meißner

Charakterisierung von Kardiomyozyten aus Herzgewebe und aus humanen Stammzellen
Maturierung humaner von pluripotenten Stammzellen abgeleiteter Kardiomyozyten (hPSC-CMs) und die Aufklärung der involvierten Signalwege
Forschungsschwerpunkt
Wir untersuchen Strategien zur Maturierung von hPSC-CMs zu einem adulten, Ventrikel-ähnlichen Phänotyp und die daran beteiligten Signalwege, vergleichend an von humanen embryonalen und humanen induzierten pluripotenten Stammzellen abgeleiteten Kardiomyozyten (hES- bzw. hiPSC-CMs, in Kooperation mit der Arbeitsgruppe von Dr. Robert Zweigerdt, LEBAO, MHH). Bemerkenswerterweise weisen hPSC-CMs eine ausgeprägte Heterogenität auf, z.B. in Hinblick auf die Expression der Isoformen des Motorproteins Myosin (MyHC), a und β. Die Expression von β-MyHC kann neben anderen Faktoren als Marker für die Maturierung der hPSC-CMs angesehen werden, da β die überwiegend im humanen ventrikulären Myokard exprimierte MyHC-Isoform ist. Der Reifungszustand von hPSC-CMs spielt eine wesentliche Rolle bei der Etablierung von Zellkultur-Modellen für kardiale Erkrankungen wie z.B. der in der Molekular- und Zellphysiologie untersuchten hypertrophen Kardiomyopathie (HCM) sowie für mögliche klinische Applikationen von hPSC-CMs in der Zellersatztherapie und für das Wirkstoff-Screening.
Die Strategien zur Förderung der Maturierung der hPSC-CMs umfassen einerseits mechanische Faktoren wie Veränderung der Steifheit der Zellkultur-Matrix und Dehnung sowie andererseits die Modifikation von beteiligten Signalwegen. Als Marker der Maturierung werden die Expression von Isoformen sarkomerischer Proteine und von Proteinen der Calciumhomöostase sowie von für das Ruhemembran- bzw. Aktionspotential relevanter Ionenkanalproteine untersucht. Bezüglich relevanter Signalwege der Maturierung der hPSC-CMs liegt der Schwerpunkt auf dem mechanosensing und der mechanotransduction, insbesondere Integrin- und Calcium-abhängige Signalwege. Auf Grund der erwähnten Heterogenität der hPSC-CMs ergibt sich die Notwendigkeit, globale Analysen der Proteinexpression- und phosphorylierung mittels Gelelektrophorese und Western Blot durch Untersuchungen auf der Einzelzell-Ebene mittels Immunfluoreszenz zu ergänzen. Desweiteren werden Genexpressionsanalysen mit Schwerpunkt auf ausgewählte kardiale Gengruppen und mechanosensing/-transduction mittels RNA sequencing, DNA oligonucleotide microarrays und qPCR durchgeführt. Die Expressionsdaten können in Zusammenarbeit mit anderen AGs des Instituts mittels einer etablierten Wiederfindungsmethode auf Einzelzell-Ebene funktionellen Parametern von Kontraktionen und Calciumtransienten zugeordnet werden.
Aktuelle Mitarbeidende
- Dr. rer. nat. Joachim Meißner
- Dr. rer.nat. Sarah Konze
- M. Sc. Felix Osten
- Cand med. Noah R. Scheller (StrukMed)
- M.Sc. Karina Ivaskevica
- Tim Holler (MTLA)
- Uwe Krumm (FH)
- Birgit Piep (VMTA)
- Behnjahwann Jasmin Kügler (FWJerin)
Ehemalige Mitarbeiter/-innen
- Dr. rer. nat. Meike Wendland
- Dr. med. Stephan Greten
- Cand. med. Simon Schulte (StrukMed)
- Neele Peschel (FWJlerin)
- Alea Bodenschatz (FWJlerin)
- Cand. med. Jan Nicolas Riesselmann (StrukMed)
- Dr. med. PhD. Natalie Weber
- Nicola Kohring (FWJlerin)
- Fatima Kaftan (FWJlerin)
- Cand med. Thomas Richard Saka Ikuye (StrukMed)
- Korf-Klingebiel M., Reboll M.R., Polten F., Weber N. , Jäckle F., Wu X., Kallikourdis M., Kunderfranco P., Condorelli G., Giannitsis E., Kustikova O.S., Schambach A., Pich A., Widder J.D., Johann Bauersachs, van den Heuvel J., Kraft T., Wang Y., Wollert K.C.Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca 2+-ATPase Expression in Cardiomyocytes, Circulation. 2021 Aug 10.doi: 10.1161/CIRCULATIONAHA.120.053365 Online ahead of print, PubMed
- Foinquinos A, Batkai S, Genschel C, Viereck J, Rump S, Gyongyosi M, Traxler D, Riesenhuber M, Spannbauer A, Lukovic D, Weber N, Zlabinger K, Hasimbegovic E, Winkler J, Fiedler J, Dangwal S, Fischer M, de la Roche J, Wojciechowski D, Kraft T, Garamvolgyi R, Neitzel S, Chatterjee S, Yin X, Bar C, Mayr M, Xiao K, Thum T. Preclinical development of a miR-132 inhibitor for heart failure treatment. Nature communications. 2020;11(1):633.
- Halloin C, Schwanke K, Lobel W, Franke A, Szepes M, Biswanath S, Wunderlich S, Merkert S, Weber N, Osten F, de la Roche J, Polten F, Christoph Wollert K, Kraft T, Fischer M, Martin U, Gruh I, Kempf H, Zweigerdt R. Continuous WNT Control Enables Advanced hPSC Cardiac Processing and Prognostic Surface Marker Identification in Chemically Defined Suspension Culture. Stem cell reports. 2019;13(2):366-79.
- Eigendorf J, May M, Friedrich J, Engeli S, Maassen N, Gros G, Meissner JD. High Intensity High Volume Interval Training Improves Endurance Performance and Induces a Nearly Complete Slow-to-Fast Fiber Transformation on the mRNA Level. Frontiers in physiology. 2018;9:601.
- Iorga B, Schwanke K, Weber N, Wendland M, Greten S, Piep B, Dos Remedios CG, Martin U, Zweigerdt R, Kraft T, Brenner B. Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms. Frontiers in physiology. 2017;8:1111.
- Kubis HP, Scheibe RJ, Decker B, Hufendiek K, Hanke N, Gros G, Meissner JD. Primary skeletal muscle cells cultured on gelatin bead microcarriers develop structural and biochemical features characteristic of adult skeletal muscle. Cell biology international. 2016;40(4):364-74.
- Al-Samir S, Wang Y, Meissner JD, Gros G, Endeward V. Cardiac Morphology and Function, and Blood Gas Transport in Aquaporin-1 Knockout Mice. Frontiers in physiology. 2016;7:181.
- Weber N, Schwanke K, Greten S, Wendland M, Iorga B, Fischer M, Geers-Knorr C, Hegermann J, Wrede C, Fiedler J, Kempf H, Franke A, Piep B, Pfanne A, Thum T, Martin U, Brenner B, Zweigerdt R, Kraft T. Stiff matrix induces switch to pure beta-cardiac myosin heavy chain expression in human ESC-derived cardiomyocytes. Basic research in cardiology. 2016;111(6):68.
- Scharf M, Neef S, Freund R, Geers-Knorr C, Franz-Wachtel M, Brandis A, Krone D, Schneider H, Groos S, Menon MB, Chang KC, Kraft T, Meissner JD, Boheler KR, Maier LS, Gaestel M, Scheibe RJ. Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate SERCA2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function. Molecular and cellular biology. 2013;33(13):2586-602.
- Al-Samir S, Papadopoulos S, Scheibe RJ, Meissner JD, Cartron JP, Sly WS, Alper SL, Gros G, Endeward V. Activity and distribution of intracellular carbonic anhydrase II and their effects on the transport activity of anion exchanger AE1/SLC4A1. The Journal of physiology. 2013;591(20):4963-82.
- Mutig N, Geers-Knoerr C, Piep B, Pahuja A, Vogt PM, Brenner B, Niederbichler AD, Kraft T. Lipoteichoic acid from Staphylococcus aureus directly affects cardiomyocyte contractility and calcium transients. Molecular immunology. 2013;56(4):720-8.
- Hanke N, Scheibe RJ, Manukjan G, Ewers D, Umeda PK, Chang KC, Kubis HP, Gros G, Meissner JD. Gene regulation mediating fiber-type transformation in skeletal muscle cells is partly glucose- and ChREBP-dependent. Biochimica et biophysica acta. 2011;1813(3):377-89.
- Meissner JD, Freund R, Krone D, Umeda PK, Chang KC, Gros G, Scheibe RJ. Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/beta gene expression via acetylation of nuclear factor of activated T cells c1. Nucleic acids research. 2011;39(14):5907-25.
- Hanke N, Kubis HP, Scheibe RJ, Berthold-Losleben M, Husing O, Meissner JD, Gros G. Passive mechanical forces upregulate the fast myosin heavy chain IId/x via integrin and p38 MAP kinase activation in a primary muscle cell culture. American journal of physiology Cell physiology. 2010;298(4):C910-20.
- Scholz ME, Meissner JD, Scheibe RJ, Umeda PK, Chang KC, Gros G, Kubis HP. Different roles of H-ras for regulation of myosin heavy chain promoters in satellite cell-derived muscle cell culture during proliferation and differentiation. American journal of physiology Cell physiology. 2009;297(4):C1012-8.
- Mallinson J, Meissner J, Chang KC. Chapter 2. Calcineurin signaling and the slow oxidative skeletal muscle fiber type. International review of cell and molecular biology. 2009;277:67-101.
- Hanke N, Meissner JD, Scheibe RJ, Endeward V, Gros G, Kubis HP. Metabolic transformation of rabbit skeletal muscle cells in primary culture in response to low glucose. Biochimica et biophysica acta. 2008;1783(5):813-25.
- Meissner JD, Umeda PK, Chang KC, Gros G, Scheibe RJ. Activation of the beta myosin heavy chain promoter by MEF-2D, MyoD, p300, and the calcineurin/NFATc1 pathway. Journal of cellular physiology. 2007;211(1):138-48.
- Meissner JD, Chang KC, Kubis HP, Nebreda AR, Gros G, Scheibe RJ. The p38alpha/beta mitogen-activated protein kinases mediate recruitment of CREB-binding protein to preserve fast myosin heavy chain IId/x gene activity in myotubes. The Journal of biological chemistry. 2007;282(10):7265-75.
- da Costa N, Edgar J, Ooi PT, Su Y, Meissner JD, Chang KC. Calcineurin differentially regulates fast myosin heavy chain genes in oxidative muscle fibre type conversion. Cell and tissue research. 2007;329(3):515-27.
- Kubis HP, Hanke N, Scheibe RJ, Meissner JD, Gros G. Ca2+ transients activate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary skeletal muscle culture. American journal of physiology Cell physiology. 2003;285(1):C56-63.
- Kubis HP, Scheibe RJ, Meissner JD, Hornung G, Gros G. Fast-to-slow transformation and nuclear import/export kinetics of the transcription factor NFATc1 during electrostimulation of rabbit muscle cells in culture. The Journal of physiology. 2002;541(Pt 3):835-47.
- Meissner JD, Gros G, Scheibe RJ, Scholz M, Kubis HP. Calcineurin regulates slow myosin, but not fast myosin or metabolic enzymes, during fast-to-slow transformation in rabbit skeletal muscle cell culture. The Journal of physiology. 2001;533(Pt 1):215-26.
- Mueller WH, Kleefeld D, Khattab B, Meissner JD, Scheibe RJ. Effects of retinoic acid on N-glycosylation and mRNA stability of the liver/bone/kidney alkaline phosphatase in neuronal cells. Journal of cellular physiology. 2000;182(1):50-61.
- Meissner JD, Kubis HP, Scheibe RJ, Gros G. Reversible Ca2+-induced fast-to-slow transition in primary skeletal muscle culture cells at the mRNA level. The Journal of physiology. 2000;523 Pt 1:19-28.
- Scheibe RJ, Kuehl H, Krautwald S, Meissner JD, Mueller WH. Ecto-alkaline phosphatase activity identified at physiological pH range on intact P19 and HL-60 cells is induced by retinoic acid. Journal of cellular biochemistry. 2000;76(3):420-36.
- Meissner JD, Naumann A, Mueller WH, Scheibe RJ. Regulation of UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosamine-1-phosphate transferase by retinoic acid in P19 cells. The Biochemical journal. 1999;338 ( Pt 2):561-8.
- Meissner JD, Brown GA, Mueller WH, Scheibe RJ. Retinoic acid-mediated decrease of G (alpha S) protein expression: involvement of G (alpha S) in the differentiation of HL-60 myeloid cells. Experimental cell research. 1996;225(1):112-21.
Publizierte Abstracts
- Weber N., Holler T., Meißner J., Montag J., Peschel N., Mayer A., Schwanke K., Piep B., Martin U., Zweigerdt R., Kraft T. Pluripotent stem cell-derived cardiomyocytes from a patient with Arg723Gly β-myosin heavy chain mutation show alterations in twitch contractions, calcium transients and highly variable allele specific expression of mutant/wildtype β-MyHC mRNA. Circulation.2019;140:A13008. AHA Scientific Sessions Conference, Philadelphia, USA, 2019.
- Kowalski K., Weber N., Holler T., Radocaj A., Fischer M., de la Roche J., Tiemann S., Schwanke K., Piep B., Lingk A., Krumm U., Martin U., Zweigerdt R., Brenner B., Kraft T. Twitch kinetics and action potential parameters are independent of expressed myosin heavy chain isoform in human stem cell-derived cardiomyocytes. Acta physiologica, October 2019, Volume 227, Issue S719, pp146-147. Deutsche Physiologische Tagung 2019.
- Schöpel G., Maier F., Weber N., Kraft T., Radocaj A., Zeug A., Fernandez J., Gutierrez J.M., Lomonte B., Loepz Davila A.J. A snake toxin phospholipase A2 homologue impairs excitation-contraction coupling and induces cell collapse in adult rat cardiomyocytes. Acta physiologica, October 2019, Volume 227, Issue S719, page 147. Deutsche Physiologische Tagung, 2019.
- Weber N., Holler T., Peschel N., Schwanke K., Piep B., Martin U., Zweigerdt R., Kraft T. Pluripotent stem cell-derived cardiomyocytes from a patient with Arg723Gly β-myosin heavy chain mutation as model for Hypertrophic Cardiomyopathy? J Muscle Res Cell Motil (2019) 40:272-273. European Muscle Conference, Canterbury, UK, 2019.
- Grunert M., Appelt S., Weber N., Huanhuan Cui, Fleur E. Mason, Niels Voigt, Silke R. Sperling. Induced pluripotent stem cell of patients with Tetralogy of Fallot reveal alterations in cardiomyocyte differentiation [version 1; not peer reviewed]. F100Research 2019, 8:1192 (poster) (doi:10.7490/f1000research.1117120.1). ISMB/ECCB, Basel, Switzerland, 2019.
- Weber N., Kowalski K., Holler T., Radocaj A., Fischer M., de la Roche J., Thiemann S., Schwanke K., Lingk A., Krumm U., Piep B, Martin U., Zweigerdt R., Brenner B., Kraft T. In human embryonic stem cell-derived cardiomyocytes twitch kinetics and action potential parameters are independent of the xpressed myosin heavy chain isoform. Biophysical Journal, Vol. 116, Issue 3, Suppl. 1, p118a. Biophysical Society Meeting, Baltimore, USA, 2019. Recipient of Travel Award from the Biophysical Society 2019.
- Lopez-Davila A.J., Weber N., Kraft T., Arias-Hidalgo M., Fernandez J., Gutierrez J.M., Lomonte B. A phospholipase A2 homologue increases the intracellular calcium concentration and induces spontaneous intracellular calcium transients and cell colapse in adult rat cardiomyocytes. Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA032. Europhysiologia, London, 2018.
- Weber N., Kowalski K., Holler T., Radocaj A., Schwanke K., Lingk A., Krumm U., Wendland M., Zywietz U., Chichkov B., Martin U., Zweigerdt R., Bernhard Brenner, Theresia Kraft. Human Embryonic Stem-Cell Derived Cardiomyocytes: Single-Cell Mapping to Relate Twitch Kinetics to Myosin Heavy Chain Protein and mRNA-Expression. Biophysical Journal 114 (3): 549a. Biophysical Society Meeting, San Fransisco, USA, 2018.
- Iorga B., Weber N., Schwanke K., Piep B., Wendland M., Greten S., Martin U., Zweigerdt R., Kraft T., Brenner B. Do β-Myosin heavy chain isoform-expressing myofibrils within human ESC-derived cardiomyocytes recapitulate the contractile features of adult human ventricular myofibrils?, J. Muscle Res. Cell. Motil., 2017, 38:391, DOI 10.1007/s10974-017-9490-8; European Muscle Conference, 2017, Potsdam, Germany
- Weber N., Kowalski K., Holler T., Lingk A., Radocaj A., Krumm U., Wendland M., Zywietz U., Chichkov B., Schwanke K., Martin U., Zweigerdt R., Brenner B., Kraft T. Single cell mapping used to assign mRNA and protein expression of cardiac myosin heavy chain to twitch kinetics of the same human embryonic stem cell derived cardiomyocyte. J Muscle Res Cell Motil 38:344. European Muscle Conference, Potsdam, GER, 2017. Young Investigator Award, 1st place.
- Weber N., Iorga B., Wendland M., Piep B., Schwanke K., Ulrich M, Zweigerdt R., Brenner B., Kraft T. Triiodothyronine induces switch to pure fast cardiac myosin heavy chain in human embryonic cardiomyocytes with significant increase in tension cost. Acta physiologica, vol. 219, Issue S711, page 134, B07-3. German Annual Physiology Society Conference, GER, 2017. Travel grant to the conference given by the German Physiology Society.
- Iorga B., Wendland M., Schwanke K., Greten S., Weber N., Martin U., Zweigerdt R., Kraft T., Brenner B. Contractile function of myofibrils within human embryonic stem cell-derived cardiomyocytes with known cardiac myosin isoform composition using a novel micromechanical approach, Acta Physiol, 2016, March, vol. 216, Suppl. S707, pg.59; 95th Deutsche Physiologische Gesellschaft Conference, 2016, Lübeck, Germany.
- Wendland M., Weber N., Greten S., Schwanke K., Iorga B., Fischer M., Geers-Knörr C., Wrede C., Hegemann J., Martin U., Brenner B., Zweigerdt R., Kraft T. Human embryonic stem cell-derived cardiomyocytes: Maturation on stiff matrix induces pure β-myosin protein expression and adult-like functional properties at the single-cell level. Acta physiologica, vol. 216, Issue S707, page 216, P22-01. German Annual Physiology Society Conference, Lübeck, 2016.
- Weber N., Iorga B., Greten S., Wendland M., Schwanke K., Martin U., Brenner B., Zweigerdt R., Kraft T. Expression of fast vs. slow cardiac myosin heavy chain in human embryonic stem-cell derived cardiomyocytes: Effects on force generation, tension cost and time course of twitches. Acta physiologoca; vol. 213, Issue S699, page 113, P114. German Annual Physiology Society Conference, Magdeburg, 2015. Travel grant to the conference given by the German Physiology Society.
- Weber N., Iorga B., Greten S., Wendland M., Schwanke K., Martin U., Brenner B., Zweigerdt R., Kraft T. Maturation towards pure β-myosin protein expression and corresponding functional properties of individual hESC-cardiomyocytes. Biophysical Journal 110(3):294a. Biophysical Society Meeting, Los Angeles, USA, 2016.
- Wendland M., Weber N., Greten S., Schwanke K., Iorga B., Fischer M., Geers-Knörr C., Wrede C., Hegemann J., Martin U., Brenner B., Zweigerdt R., Kraft T. Human embryonic stem cell-derived cardiomyocytes: Maturation on stiff matrix induces pure β-myosin protein expressionand adult-like functional properties at the single-cell level. Acta physiologica, vol. 216, Issue S707, page 216, P22-01. German Annual Physiology Society Conference, Lübeck, 2016.
- Weber N., Iorga B., Greten S., Wendland M., Schwanke K., Martin U., Brenner B., Zweigerdt R., Kraft T. Expression of fast vs. slow cardiac myosin heavy chain in human embryonic stem-cell derived cardiomyocytes: Effects on force generation, tension cost and time course of twitches. Acta physiologoca; vol. 213, Issue S699, page 113, P114. Travel grant to the conference given by the German Physiology Society. German Annual Physiology Society Conference, Magdeburg, 2015.
- Mutig N., Geers-Knörr C., Piep B., Pahuja A., Vogt P.M.,Brenner B., Niederbichler A.D., Kraft T. Early stimulating and late inhibiting effects of lipoteichoic acid on adult cardiomyocyte contractility and calcium transients. Acta physiologica; vol. 210, Issue S695, page 160, P 203. German Annual Physiology Society Conference, Mainz, 2014.
- Dr. Joachim Meißner
Leitung von Praktika für Human- und Zahnmediziner/-innen sowie Biologen/-innen zu diversen physiologischen Themen.
Leitung von Seminaren für Humanmediziner/-innen zu diversen physiologischen Themen.
- Felix Osten
Leitung von Praktika für Human- und Zahnmediziner/-innen sowie Biologen/-innen zum Thema Muskel.