Development Biology Group at the Department for Medical Biochemistry,Max F. Perutz Laboratories, Vienna Bio Center, Medical University Vienna, Austria
Current coworkers: Theresa Matzinger MSc,CTA Franziska Hofstätter, Florian Steiner, Claudia Rudolf, CTA, Julia Kober, Maximilian SeitlWe are interested firstly, in the influence of growth factors on cardiomyogenesis and on proliferation of heart cells in culture from the outside of cardiomyocytes and secondly, in the influence of the intermediate filament protein desmin on development and maintenance of the myocardial phenotype from inside the myocardial cell. Understanding the molecular mechanism triggering and maintaining heart cell development will allow to establish heart cell culture for pharmacological tests and mass production for cell therapy of the myocardium. In parallel to the generation of cardiomyocytes from embryonic stem cells we seek to identify, isolate and maintain somatic cardioblast-like stem cells which upon stimulation with growth factors differentiate to committed and well differentiated cardiomyocytes which can be used for cell therapy.
In the past we investigated the role of desmin in mice (Milner et al., 1996) and in embryoid bodies (Weitzer et al., 1995) faithfully mimicking pre-gastrulation and early gastrulation of embryos (Weitzer, 2005). Generation of various mutant desmin alleles by homologous recombination techniques (Höllrigl et al., 2001) allowed to demonstrate specific roles of the amino-terminal domain of desmin during early cardiomyogenesis (Höllrigl et al., 2002).
Investigating signals influencing cardiomyogenesis in a paracrine mode we firstly focused on LIF, which turned out to modulate cardiomyogenesis in an opposite and developmental stage dependent manner (Bader et al., 2000; Bader et al., 2001), then identified two new factors secreted by parietal endoderm, SPARC and S100A4 which promote cardiomyogenesis differentially (Stary et al., 2005). The mechanism of their signalling in cardiomyocytes is currently under investigation.
Finally, we succeeded in the generation of multiple isogenic monoclonal embryonic stem cell lines from single inner cell masses, which allowed us to demonstrate that epigenetic differences in the expression level of lifr predetermine the developmental potential of embryonic stem cells in a JAK2 dependent manner (Lauss et al., 2005). This demonstrated for the first time that isogenic stem cells do not equally well contribute to cardiomyogenesis, and thus not all existing human embryonic stem cells will be equally well suitable for future cell therapy. Further, theye cell lines all have the intrinsic information who gastrulation takes place when aggregated: In embryoid bodies a bilateral symetry is formed, which is brooken during the development of first cardiomyytes (Fuchs et al., 2012). Notably, this information is lost in cardiovascular progenitor cells, where more cardiomyocytes develop, however, in a unstructured manner.
Currently, after having identified desmin as a transcription-cofactor influencing nkx2.5 expression in cardiac stem cells, we investigate the mutual influence of SPARC, Desmin and Nkx2.5 in blancing self-renwal and differentation of cardiac stem cells
Publications:
Fuchs C., Scheinast M., Pasteiner W., Lagger S., Hofner M., Höllrigl A., Schultheis M., Weitzer G. Self-organisation phenomena in embryonic stem cell derived embryoid bodies: Axis formation and breaking of symmetry during cardiomyogenesis. (2012) Cells Tissues and Organs. Online published on August 19th 2011. DOI: 10.1159/000328712 link
Lagger,S, Meunier,D, Mikula,M, Brunmeir,R, Schlederer,M, Artaker,M, Pusch, O, Egger,G, Hagelkruys,A, Mikulits,W, Weitzer,G, Muellner,EW, Susani,M,Kenner, L, and Seiser, C (2010) Crucial function of histone deacetylase 1 for differentiation of Teratomas in mice and humans. EMBO J 21, 2672-2681.
Zupkovitz, G., Grausenburger, R., Brunmeir, R., Tischler, T., J., J., Rembold, M., Meunier, D., Egger, G., Lagger, S., Propst, F., Weitzer, G. and Seiser, C. (2010). The cyclin dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cell proliferation. Mol Cell Biol 30, 1171-1181.
Weitzer, G. (2008) Medical applications of stem cell therapy: visions and reality. In Stammzellforschung, Schriftenreihe Ethik und Recht in der Medizin Band 2, Eds. Körtner U.H.J. and Kopetzki, C., M. Springer Wien New York. ISBN 978-3-211-77511-0 link
Hofner, M., Höllrigl, A., Puz, S., Stary, M., and Weitzer, G. (2007). Desmin stimulates differentiation of cardiomyocytes and upregulation of brachyury and nkx2.5. Differentiation 75, 605-615. link
Höllrigl, A., Hofner, M., Stary, M., and Weitzer, G. (2007). Differentiation of cardiomyocytes requires functional serine residues within the amino-terminal domain of desmin. Differentiation 75, 616-626. link
Stary. M., Schneider, M., Sheikh, S.P., Weitzer, G. (2006) Parietal endoderm secreted S100A4 promotes early cardiomyogenesis in embryoid bodies. Biochem Biophys Res Commun, 343, 555-563.link
Weitzer, G. (2006) Embryonic stem cell-derived embryoid bodies - an in vitro model for eutherian pregastrulation development and early gastrulation.Handbook of Experimental Physiology, Special Issue Stem Cells, 174, 21-51.
Stary, M., W. Pasteiner, A. Summer, A. Hrdina, A. Eger, and G. Weitzer. 2005. Parietalendoderm secreted SPARC promotes early cardiomyogenesis in vitro. Exp Cell Res. 310, 331-343.link
Lauss, M., Stary, M., Tischler, J., Egger, G., Puz, S., Bader-Allmer, A., Seiser, C., and Weitzer, G. (2005) Single inner cell masses yield embryonic stem cell lines differing in lifr expression and their developmental potential. Biochem Biophys Res Commun. 331, 1577-1586.
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Höllrigl, A., Puz, S., Al-Dubai, H., H., Kim, J.U., Capetanaki, Y., and Weitzer, G. (2002) Amino-terminally truncated desmin rescues fusion of des-/- myoblasts but negatively affects cardiomyogenesis and smooth muscle development. FEBS Letters 26285, 229-233.
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Lagger, G., O´Carroll, D., Rembold, M., Khier, H., Tischler, J., Weitzer, G., Schuettengruber, B., Hauser, Ch., Brunmeir, R., Jenuwein, T., and Seiser, C. (2002)
Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO Journal 21, 2672-2681.
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Höllrigl, A., Hergovich, A., Görzer, I., Bader, A., Ellersdorfer, G., Habegger,
K., Hammer, E., Enzinger, S., Capetanaki, Y. and Weitzer, G. (2001)
High-throughput site-directed mutagenesis in ES cells. Biochem Biophys Res Commun 289, 329-336.
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Bader, A., Gruss, A., Höllrigl, A., Al-Dubai, H., Capetanaki, Y. and
Weitzer, G. (2001)Paracrine promotion of cardiomyogenesis in embryoid bodies
by LIF modulated endoderm. Differentiation 68, 32-43. link
Bader, A., Al-Dubai, H., and Weitzer, G. (2000) Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circulation Research 86, 787-794. link
Hofner, M., Höllrigl, A., Puz, S., Stary, M., and Weitzer, G. (2007). Desmin stimulates differentiation of cardiomyocytes and upregulation of brachyury and nkx2.5. Differentiation,online publication March 23rd. link
Höllrigl, A., Hofner, M., Stary, M., and Weitzer, G. (2007). Differentiation of cardiomyocytes requires functional serine residues within the amino-terminal domain of desmin. Differentiation,online publication March 23rd. link
Höllrigl, A., Puz, S., Al-Dubai, H., H., Kim, J.U., Capetanaki, Y., and Weitzer, G. (2002) Amino-terminally truncated desmin rescues fusion of des-/- myoblasts but negatively affects cardiomyogenesis and smooth muscle development. FEBS Letters 26285, 229-233.
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Capetanaki, Y., Millner, D.J., and Weitzer G. (1997) Desmin in muscle formation and maintenance: Knockouts and consequences. Cell Structure and Function 22, 103-116.
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Milner, D.J, Weitzer, G., Tran, D., Bradley, A., Capetanaki, Y. (1996) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. Journal Cell Biology 134, 1255-1270.
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Weitzer, G., Milner, D.J., Kim, J.U., Bradley, A., and Capetanaki, Y. (1995) Cytoskeletal control of myogenesis: A desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. Developmental Biology 172, 422-439.
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