Group name: Meyer Group
Group leader: Morten Meyer
Group members: 1 Research assistant, 4 Ph.D. students, 1 Technician (B.Sc. and M.Sc. students not included).
Department & University/Hospital/Other: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark.
Funding sources: The Danish Parkinson Foundation, Innovation Fund Denmark, H. Lundbeck A/S, IMK Almene Fond (minor foundations not included).
Description of research:
Our research group is a subgroup within a larger, internationally recognized research unit, with strong international and industrial relations, focusing on injury, protection and repair of CNS nerve cells and glial cells using in vitro and animal models of disease.
The major effort of our group is devoted to harnessing and manipulating the differentiation potential of human neural stem cells and induced pluripotent stem cells. Our research program is focused on identifying molecular and biochemical signals regulating cell fate decisions. We place particular emphasis on formation of functional dopaminergic neurons with midbrain characteristics - the cell type that degenerates in Parkinson’s disease.
Using stem cells and dopaminergic neurons derived from developing human brain tissue (neural stem cells) and patients with sporadic or familial Parkinson’s disease (induced pluripotent stem cells), our main current effort is on:
a) investigation of the early cellular changes that underlie the onset of neurodegeneration in
familial Parkinson’s disease (cells with and without PARK2 muations). This includes the use of isogenic stem cells in combination with molecular assays and advanced mass spectometry-based methods (proteomics, metabolomics and lipidomics - including post-translational
modifications).
b) validation of stem cell-derived human dopaminergic neurons in a hemiparkinsonian rat model of Parkinson’s disease. This includes long-term survival of transplanted cells to assess cell fate, maturation and integration, as well as functional behavioural assessment for graft function.
Our general ambitions are to advance the understanding of the molecular mechanisms
underlying Parkinson’s disease and to contribute to the development of a potential future
stem cell therapy.
Key publications (last 10 years):
1. Jensen P., Bauer M., Jensen C.H, Widmer H.R., Gramsbergen J.B., Blaabjerg M., Zimmer J., Meyer M. (2007) Expansion and characterization of ventral mesencephalic precursor cells: Influence of mitogens and investigation of FA1 as a potential dopaminergic marker (J. Neurosci. Research 85: 1884-1893).
2. Andersen R. K., Johansen M., Blaabjerg M., Zimmer J., and Meyer M. (2007) Neural tissue-spheres: A microexplant culture method for propagation of precursor cells from the rat forebrain subventricular zone (Journal of Neuroscience Methods 165: 55-63).
3. Anwar M.R., Andreasen C.M., Lippert S.K., Zimmer J., Martinez-Serrano A., Meyer M. (2008) Dopami-nergic differentiation of human neural stem cells mediated by cocultured rat striatal brain slices (Journal Neurochemistry 105: 460-470).
4. Andersen R. K., Zimmer J., Wahlberg L. U., Meyer M. (2008) Effect of leukemia inhibitory factor on long-term propagation precursor cells derived from rat forebrain subventricular zone and ventral mesencepha-lon (Experimental Neurology 211: 301-310).
5. Jensen P., Pedersen E.G., Zimmer J., Meyer M. (2008) Functional effect of FGF2- and FGF8-expanded ventral mesencephalic precursor cells in a rat model of Parkinson’s disease (Brain Research 1218: 13-20).
6. Krabbe C., Courtois E., Jensen P., Jørgensen J. R., Zimmer J., Martínez-Serrano A., Meyer M. (2009) En-hanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension (Journal of Neurochemistry 110: 1908-1920).
7. Tanvig M., Blaabjerg M., Andersen R.K, Villa A., Rosager A.M., F.R. Poulsen, Martinez-Serrano A., Zim-mer J., Meyer M. (2009). A brain slice culture model for studies of endogenous and exogenous precursor cell migration in the rostral migratory stream (Brain Research 1295: 1-12).
8. Andersen, R.K., Widmer, H. R., Wahlberg L. U., Zimmer, J., Meyer, M. (2009) Leukemia inhibitory factor induces tyrosine hydroxylase expression in long-term propagated human midbrain precursor cells (Neu-roscience Letters 464: 203-208).
9. Jensen P., Gramsbergen J.B., Zimmer J., Widmer H.R., Meyer M. (2011). Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension (Exp. Cell Research 317: 1649-1662).
10. Jensen P.S., Lyck L., Jensen P., Zimmer J., Meyer M. (2012). Characterization of porcine ventral me-sencephalic precursor cells following long-term propagation in 3D culture (Stem Cells Int. 2012: 761843).
11. Jensen P., Heimberg M., Ducray A.D., Widmer H.R., Meyer M. (2013). Expression of Trefoil factor 1 in the developing and adult rat ventral mesencephalon (PLoS ONE, DOI 10.1371/journal.pone.0076592).
12. Krabbe C., Thornby Bak S., Linstow C.U., Jensen P., Martinez-Serrano A., Hansen C., Meyer M. (2014). Influence of oxygen tension on dopaminergic differentiation of human fetal stem cells of midbrain and fore-brain origin (PLoS ONE. DOI 10.1371/journal.pone.0096465).
13. Erichsen J.L., Blaabjerg M., Bogetofte H., Martinez Serrano A., Meyer M. (2015). Group I Metabotropic Glutamate Receptors: A Potential Target for Regulation of Proliferation and Differentiation of an Immortal-ized Human Neural Stem Cell Line (Basic & Clinical Pharmacology & Toxicology, 116, 4, 329-336).
14. Jensen P., Ducray A.D., Widmer H.R., Meyer M. (2015). Effects of forskolin on trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons (Neuroscience: DOI 10.1016/ j.neuroscience. 2015.10.010).
15. Momcilovic O., Sivapatham R., Oron T.R., Meyer M., Mooney S.D., Rao M., Zeng X. (2016). Derivation, characterization, and neural differentiation of integration-free induced pluripotent stem cell lines from Par-kinson’s disease patients carrying SNCA, LRRK2, PARK2, and GBA mutations (PLoS ONE, DOI 10.1371/journal.pone.0154890).
16. Holmqvist S., Lehtonen Š., Chumarina M., Puttonen K.A., Azevedo C., Lebedeva O., Ruponen M., Oksanen M., Dejlloul M., Collin A., Goldwurm S., Meyer M., Lagarkova M., Kiselev S., Koistinaho J., Roybon L. (2016). Creation of a library of induced pluripotent stem cell models from Parkinsonian patients (NPJ Par-kinson’s Disease, DOI 10.1038/npjparkd.2016.9).
17. Zhang Y., Schmid B., Nikolaisen N.K., Rasmussen M.A., Aldana B.I., Agger M., Calloe K., Stummann T.C., Larsen H.M., Nielsen T.T., Huang J., Xu F., Liu X., Bolund L., Meyer M., Bak L.K., Waagepetersen H.S., Lou Y., Nielsen J.E., Thre FReJA Consortium, Holst B., Clausen C., Hyttel P., Freude K.K (2017). Patient
18. iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B (Stem Cell Reports, DOI: http://dx.doi.org/10.1016/j.stemcr.2017.01.012).
19. Perez-Bouza, A., Di Santo, S., Seiler, S., Meyer, M., Andereggen, L., Huber, A., Guzman, R., Widmer, H. R. (2017). Simultaneous transplantation of fetal ventral mesencephalic tissue and encapsulated genetically modified cells releasing GDNF in a hemi-parkinsonian rat model of Parkinson's disease (Cell Transplanta-tion, DOI: 10.3727/096368917X694679).
Other outputs:
Lambertsen KL, Clausen BH, Meyer M (equal contributors) (2015) Tnf-alpha inhibitor for treating stroke.
Patent No: WO2016078672 A1, PCT/DK2015/050358.
Key collaborations:
Danish:
Drs. Poul Hyttel, Kristine Freude, Vanessa Jane Hall, University of Copenhagen.
Drs. Karina Fog, Tina Charlotte Stummann, H. Lundbeck A/S.
Dr. Morten Blaabjerg, University Hospital Zealand.
Dr. Poul Henning Jensen, Aarhus University.
Drs. Frantz R. Poulsen, Bjarne Winther Kristensen, Lene Wermuth, Odense University Hospital.
Drs. Kate Lykke Lambertsen, Åsa Fex Svenningsen, University of Southern Denmark.
Drs. Martin Røssel Larsen, Nils J. Færgeman, Christer Ejsing, University of Southern Denmark.
International:
Drs. Richard Wade-Martins, Brent Ryan, Oxford University, UK.
Dr. Laurent Roybon, Lund University, S.
Dr. Xianmin Zeng, Buck Institute, USA.
Dr. Alberto Martinez-Serrano, Autonomous University of Madrid, E.
Dr. Hans R. Widmer, University Hospital of Bern, CH.
Dr. Raphael Guzman, University Hospital Basel, CH.
Infrastructure:
Human neural stem cell lines (forebrain, midbrain)
Induced pluripotent stem cell lines (Parkinson patient/controls)
Isogenic induced pluripotent stem cell lines (PARK2 mutation vs. control)
Human brain tissue (sporadic Parkinson’s disease, healthy fetal and adult)
3-D neurosphere cultures (forebrain subventricular zone)
Organotypic brain slice cultures (ventral mesencephlon, striatum, hippocamus)
Microtransplantation of brain slice cultures (in vitro model of cell grafting)
Animal model of Parkinson’s disease (6-OHDA), stereotactic cell transplantation, behavioral analyses (motor assessment and cognition).
Various histological, immunological and biochemical techniques (e.g. cytochemistry, imunocy-tochemistry, in situ hybridization, Western blotting, enzyme assays, HPLC analysis, multiplex cytokine arrays, calcium imaging).