Matthias Löhle

Project description

In 2006, Takahashi and Yamanaka for the first time reported that mouse embryonic and adult fibroblasts acquired the morphology and growth properties of embryonic stem cells after retroviral introduction of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc. The authors called these cells, which also showed expression of embryonic stem cell marker genes after reprogramming, induced pluripotent stem (iPS) cells. Due to their ability to self-renew and to differentiate into any cell type of the body, iPS cells will presumably become a powerful source for cell replacement therapy in various diseases. In the current project, we are focusing on examining the neuronal differentiation potential of these cells, whose investigation is a major precondition for their future use in neurodegenerative diseases, such as Parkinson’s disease.

 

 

Curriculum vitae


Dr. med. Matthias Löhle

Department of Neurology

University Hospital Carl Gustav Carus

Dresden University of Technology

Fetscherstrasse 74

01307 Dresden

Personal data

Date of birth: April 29th, 1977

Place of birth: Jena

Nationality: German

Marital status: Single

Academic qualifications

License to practice medicine: October 22nd, 2002

Friedrich Schiller University Jena

M.D.: May 31st, 2005

Friedrich Schiller University Jena

Thesis title: “The influence of a prenatal glucocorticoid therapy on fetal cerebral blood flow and cerebral autoregulation in different gestational ages.”

Professional experience

2003-2004: Research Scholar for the Department of Obstetrics & Gynecology, New York University, USA and at the Center for the Study of Fetal Programming, University of Wyoming, USA

Supervisor: Prof. Peter Nathanielsz, M.D., Ph.D., Sc.D., FRCOG

2004-2005: Elective period at the Department of Neurology at the “Kantonspital St.Gallen”, St.Gallen, Switzerland.

since 2005: Assistant doctor at the Department of Neurology, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

Member of the Group for Neuroregeneration

Supervisor: Prof. Alexander Storch, M.D., Ph.D.

Clinical specialties: Parkinson’s disease, Huntington’s disease, atypical Parkinson syndromes, tremor, ataxia and dystonia

 

Publications

 

1) Loehle M, Schwab M, Kadner S, Maner KM, Gilbert JS, Brenna JT, Ford SP, Nathanielsz PW, Nijland MJ. Dose-response effects of betamethasone on maturation of the fetal sheep lung. Am J Obstet Gynecol. 2010 Feb;202(2):186.e1-186.e7.

2) Löhle M, Reichmann H. Clinical neuroprotection in Parkinson's disease - still waiting for the breakthrough. J Neurol Sci. 2010;289(1-2):104-14.

3) Reichmann H, Schneider C, Löhle M. Non-motor features of Parkinson's disease: depression and dementia. Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S87-92.

4) Löhle M, Storch A, Reichmann H. Beyond tremor and rigidity: non-motor features of Parkinson's disease. J Neural Transm. 2009;116(11):1483-92.

5) Wolz M, Kaminsky A, Löhle M, Koch R, Storch A, Reichmann H. Chocolate consumption is increased in Parkinson's disease. Results from a self-questionnaire study. J Neurol. 2009;256(3):488-92.

6) Grosset D, Antonini A, Canesi M, Pezzoli G, Lees A, Shaw K, Cubo E, Martinez-Martin P, Rascol O, Negre-Pages L, Senard A, Schwarz J, Strecker K, Reichmann H, Storch A, Löhle M, Stocchi F, Grosset K. Adherence to antiparkinson medication in a multicenter European study. Mov Disord. 2009;24(6):826-32.

7) Löhle M, Storch A. Orally disintegrating selegiline for the treatment of Parkinson's disease. Expert Opin Pharmacother. 2008;9(16):2881-91.

8) Wolz M, Junghanns S, Löhle M, von Kummer R, Storch A. Dystonia associated with hyperintense basal ganglia lesions on T1-weighted brain MRI. Mov Disord. 2008;23(11):1618-9.

9) Löhle M, Schrempf W, Wolz M, Reichmann H, Storch A. Potassium channel blocker 4-aminopyridine is effective in interictal cerebellar symptoms in episodic ataxia type 2--a video case report. Mov Disord. 2008;23(9):1314-6.

10) Frasch MG, Müller T, Wicher C, Weiss C, Löhle M, Schwab K, Schubert H, Nathanielsz PW, Witte OW, Schwab M. Fetal body weight and the development of the control of the cardiovascular system in fetal sheep. J Physiol. 2007;579(Pt3):893-907.

11) Samtani MN, Löhle M, Grant A, Nathanielsz PW, Jusko WJ. Betamethasone pharmacokinetics after two prodrug formulations in sheep: implications for antenatal corticosteroid use. Drug Metab Dispos. 2005;33(8):1124-30.

12) Löhle M, Müller T, Wicher C, Roedel M, Schubert H, Witte OW, Nathanielsz PW, Schwab M. Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary-adrenal axis. J Physiol. 2005;564(Pt 2):575-88.

13) Müller T, Löhle M, Schubert H, Bauer R, Wicher C, Antonow-Schlorke I, Sliwka U, Nathanielsz PW, Schwab M. Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex. J Physiol. 2002;539(Pt 3):957-67.

Andreas Hermann

Characterization and manipulation of the stem cell niche in the adult midbrain.
Since the early 90ies neurogenesis in the adult mammalian brain is well known. However, this is restricted to two regions within the adult brain, namely the subventricular zone (SVZ) of the lateral ventricles as well as the dentate gyrus (DG) of the hippocampus. We recently showed the excistance of neural stem cells (NSCs) also in the midbrain. In contrast to NSCs from the SVZ or the DG these midbrain-derived adult NSCs can be differentiated to functional dopaminergic neurons. However, these midbrain NSCs do not proliferate in vivo representing most likely dormant progenitor cells (Hermann 2006a, 2009).
The aim of our work is to elucidate whether the differences between midbrain-derived NSCs and NSCs from the SVZ or DG are due to cell intrinsic mechanisms or whether cell extrinsic signals from the surrounding brain tissue suppress in vivo neurogenesis in the midbrain. Furthermore our efforts focus on manipulation of the stem cell niche within the midbrain aiming on the activation of these dormant NSCs as a cell source for endogenous cell replacement strategies, e.g. in Parkonson’s disease (Hermann 2008).
 
 
Characterization of adult neural stem cells within the adult human brain.
Adult neurogenesis in the human brain was finally proven in the early 90ies. Interestingly, the human neurogenic regions differ from their mouse counterparts. This is most obvious in the architecture of the human subventricular zone (SVZ) of the lateral ventricles. Major differences are decreased rapid amplifying cells as well as a representative bulbus olfactorius as target for the newly generated neurons. Of note is however the discovery of progenitor cells within the white matter, so called oligodenrocyte progenitor cells (OPCs). These are easy to isolate and behave like typical NSCs in vitro generating astrocytes, oligodendrocytes and neurons. We recently showed that most of NSCs isolated from the adult human hippocampus are such OPCs. Since these cells are already regionalized, possessing properties of the region of isolation, these hippocampal NSCs cannot produce dopamine nerve cells (Hermann 2006b, Maisel 2007).
The aim of our work is the exact characterization of these OPCs-NSCs from the human brain in vivo and in vitro. A special focus is drawn on transcription factors involved in neuronal differentiation (e.g. SOX2, OLIG2). Futhermore we are working on approaches for manipulation of these human NSCs to become dopamine neurons. Thereby these human NSCs might be a potential cell source for autologous cell replacement therapies for example in Parkinson’s disease.

 
Name:Andreas Hermann
Born:4th August, 1978
 
Education:
Februar, 2007
PhD defense (Doktor der biomedizinischen Wissenschaften /Dr. rer. med.) about: “In vitro neurogenesis of adult neural stem cells from bone marrow and brain.“ University of Ulm, Germany
October, 2005 Approbation as medical doctor, Dresden University of Technology, Germany

 
 
Research and Clinical Experience:

01/2007-07/09 Seed grant of the Center for Regenerative Therapies Dresden (CRTD)
12/2005- present Resident in the Department of Neurology, Technical University Dresden
10/2004- present Research in Experimental Neurology, Technical University Dresden, Research group Neurodegeneration and Neuroregeneration (group leader: Prof. Alexander Storch, M.D.)
8/03-11/03
Practical course about “Mouse and human embryonic stem cell culture including
dopaminergic differentiation and transplantation in animal models of Parkinson’s disease” in the Molecular Biology Laboratories of Kwang-Soo Kim, McLean Hospital, Harvard Medical School, Boston, MA, USA

 

Literatur:

Meyer AK, Longin CF, Klose C, Hermann A. New regulator for energy signaling pathway in plants highlights conservation among species. Sci Signal. 2010 Apr 27;3(119):jc5.
Hermann A, Suess C, Fauser M, Kanzler S, Witt M, Fabel K, Schwarz J, Höglinger GU, Storch A.Rostro-Caudal Gradual Loss of Cellular Diversity Within The Periventricular Regions of The Ventricular System. Stem Cells, 2009;Accepted Article Online: DOI: 10.1002/stem.21
 
Hermann A, Storch A. Endogenous regeneration in Parkinson's disease: do we need orthotopic dopaminergic neurogenesis?Stem Cells, 2008; 26(11):2749-5
 
Maisel M, Herr A, Milosevic J, Hermann A, Habisch HJ, Schwarz S, Kirsch M, Antoniadis G, Brenner R, Hallmeyer-Elgner S, Lerche H, Schwarz J, Storch A. Transcription profiling of adult and fetal human neuroprogenitors identifies divergent paths to maintain the neuroprogenitor cell state. StemCells, 2007, 2007 May;25(5):1231-40
 
Hermann A, Maisel M, Liebau S, Gerlach M, Kleger A, Schwarz J, Kim KS, Antoniadis G, Lerche H, Storch A: Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells. Journal of Neurochemistry, 2006; 98(2): 629-640.
 
Hermann A, Maisel M, Wegner F, Liebau S, Kim DW, Gerlach M, Schwarz J, Kim KS, Storch A: Multipotent Neural Stem Cells from the Adult Tegmentum with Dopaminergic Potential Develop Essential Properties of Functional Neurons. Stem Cells 2006, 24(4): 949-64.

Anne K. Meyer

Characterization of fetal mouse neural stem cells.

 

 

 

Neural stem (progenitor) cells (NPCs) from fetal tissue are an ideal transplantable cell source. They divide rapidly, are able to generate cells of all three neural lineages and do not divide uncontrolled once transplanted into a host organism. To obtain large quantities of cells for transplantation strategies and to eliminate primary cell contaminations, long periods of in vitro cultivation are necessary.

 

Mouse NPCs are a crucial tool for further investigations of neural stem cells because they make the employment of transgenic animals in vivo and cells in vitro possible. So far only short-term expanded fetal mouse NPCs have been shown to generate dopaminergic neurons and it is not clear whether this was due to differentiation or a result of increased survival of primary dopaminergic neurons.

 

Long-term expanded fetal mesencephalic NPCs can be grown under suspension and adherent culture conditions and show self-renewing capacity as well as markers typical for NPCs.




I focus on two coherent issues: the precise characterization of progenitor populations to find out which in vitro conditions need to be provided to keep the balance between proliferation and differentiation potential. I also want to prove true differentiation of dopaminergic neurons in vitro. The knowledge gained about stem cells this way would help establish cell sources for transplantation strategies.

Role of Lrrk2 in controlling the phenotype of predopaminergic neural stem cells.

 

 

 

A recent key finding in Parkinson’s disease was the identification of the protein kinase LRRK2 (also referred to as PARK8) as a causative gene for sporadic as well as autosomal-dominant familial parkinsonism. At present, a unifying hypothesis for the pathogenic mechanisms of Lrrk2 protein is still sought after.

 

However, we found first evidence for the involvement of Lrrk2 in controlling the proliferation/cell cycle of predopaminergic neural stem cells (NSCs).

 

The objectives of the present project are to study the role of physiological, wild-type Lrrk2 in predopaminergic progenitor cells and to develop a relevant cell culture model of Parkinson’s disease by using over-expression of a mutated form of the Lrrk2 gene. I investigate the effects of Lrrk2 expression and mutation on proliferation, differentiation and survival of mouse predopaminergic NSCs.

These data will allow us to dissect the actions of Lrrk2 during the development of the dopaminergic system.

CV:
Name:                Anne K. Meyer

 

Education:

2009  Dr. rer. nat. (Biologie) at TU Dresden about: „Intracellular signaling pathways in the dopaminergic specification of fetal mesencephalic stem cells.“
2004 Dipl.-Ing. (Biotechnologie) at TU Berlin.
 
Research experience: 
 
2009-present Postdoc in Experimental Neurology (AG Storch)
2004-2009 Ph.D. Thesis in Experimental Neurology; (AG Storch)
2003/04 Diploma Thesis at Max-Planck-Institute for Molecular Genetics, Berlin, Germany (AG Scharff/AG Vingron)
2003 Student Research Project, Dept. Microbiology and Genetics at TU Berlin, Germany
 
Literatur:

 

Meyer AK, Maisel M, Hermann A, Stirl K, Storch A.
J Neurol Sci. 2009 Sep 3. [Epub ahead of print]

 

Sabolek M, Baumann B, Heinrich M, Meyer AK, Herborg A, Liebau S, Maisel M, Hermann A, Ventz K, Schwarz J, Wirth T, Storch A.

Stem Cells. 2009 Aug;27(8):2009-21.

 

Milosevic J, Schwarz SC, Ogunlade V, Meyer AK, Storch A, Schwarz J.

Mol Neurodegener. 2009 Jun 15;4:25.

Moritz Brandt

Adult neurogenesis in a genetic mouse model of Parkinsons disease

The generation of new neurons in the adult dentate gyrus has functional implications for the hippocampal formation. Reduced hippocampal neurogenesis has been described in different animal models of hippocampal dysfunction like dementia or depression. Dementia and depression are common non-motor-symptoms of Parkinsons disease (PD). As dopamine (DA) plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN) in PD has been brought into connection with reduced neurogenesis in the neurogenic regions of the adult brain: subventricular zone (SVZ) and dentate gyrus (DG). We are examining adult hippocampal neurogenesis in Pitx3-mutant-mice, which phenotypically show an selective degeneration of DA neurons of the SN, while the ventral tegmental area (VTA) is unaffected in young animals and partial degenerates during adulthood. This genetic PD-animal-model gives us the opportunity to differentially investigate the influence of the SN and VTA on adult neurogenesis.

 

Hypoxia related signaling in adult hippocampal precursor cells

Oxygen-related gene expression is reported crucial for affecting stem and progenitor cell behavior with hypoxia-inducible factor-1a (HIF-1α) as one major oxygen-sensing molecule regulating several genes involved in neurogenesis, such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO). Another important oxygen-sensitive signaling pathway is the intracellular Notch1 pathway. Notch has multiple function during all steps of neuronal development: e.g. stem-cell maintenance, inhibition of neuronal differentiation, survival and dendritic maturation of postmitotic neurons. The aim of our project is to investigate the role of Notch1, VEGF and other hypoxia-inducible factors in adult hippocampal neurogenesis. We are using voluntary exercise (wheel running) as a well-established physiological stimulator of adult neurogenesis to investigate the expression of hypoxia related genes and growth-factors in vivo. Furthermore, we take advantage of two knock-out models that lack the expression of VEGF-receptor type 2 (flk1) and Hif-1a respectively in neural progenitor cells.
 
 
Cell cycle kinetics in adult hippocampal neurogenesis

Stem and precursor cells of the adult hippocampus show differences in mitotic frequency and length of cell cycle phases. Depending on the developmental stage they divide symmetrically or asymmetrically. Thus the pool of proliferating cells in the subgranular zone of the hippocampus is very heterogeneous regarding mitotic activity and the production of progenies. Our aim is to investigate the cell specific cell cycle characteristics of different precursor populations.
 





 
The relation of sleep and cellular plasticity in the hippocampus
 

Translationale Forschung (HICH-Studie)

 


 
Curriculum Vitae                            Dr. med. Moritz Brandt
 
 
Personal
 
 
Name:                         Moritz Daniel Brandt
Date of birth:               October 17th, 1977
Place of birth:              Essen, Germany
Email:                            Diese E-Mail-Adresse ist vor Spambots geschützt! Zur Anzeige muss JavaScript eingeschaltet sein!
 



Education
 
 
 
1998-2006             Medical student at the University of Leipzig and Humboldt-University Berlin (Charité)
2001-2003             Thesis at the Max-Delbrück-Center for Molecular Medicine, Berlin.
Research group “Neuronal Stem Cells” (Prof. Dr. Gerd Kempermann)
07/2006                 State examination (Staatsexamen) and doctoral degree
Thesis title: Adulte Neurogenese im murinen Hippocampus: Phasenspezifische Calretininexpression in unreifen Neuronen.
Since 11/2006        Resident (Arzt in Weiterbildung) at the Department of Neurology, Carl Gustav Carus Universitätsklinikum Dresden.
                            Clinicalfocus:Neurological sleep disorders
                            Postdoc research group “Neuroregeneration” (Prof. Dr. A. Storch)

 

Publications
 
 
Brandt MD, Maass A, Kempermann G, Storch A.
Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis..
Eur J Neurosci. 2010 Oct; 32(8):1256-64
 
Hermann A, Brandt MD, Loewenbrueck KF, Storch A.
“Silenced” polydendrocytes: A new cell type within the oligodendrocyte progenitor cell population?
Cell Tissue Res. 2010 Apr; 340(1): 45-50. Review
                                                          
Brandt MD, Storch A.
Neurogenesis in the adult brain: from bench to bedside?.
Fortschr Neurol Psychiatr. 2008 Sep; 76(9):517-29. Review
 
Plümpe T, Ehninger D, Steiner B, Jessberger S, Klempin F, Brandt MD, Römer B, Rodriguez GR, and Kempermann G.
Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation.
BMC Neurosci. 2006 Nov 15;7:77.
 
Steiner B, Kronenberg G, Jessberger S, Brandt MD, Reuter K, Kempermann G.
Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice.
Glia. 2004 Apr 1;46(1):41-52.
 
Kronenberg G, Reuter K, Steiner B, Brandt MD, Jessberger S, Yamaguchi M, Kempermann G.
Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli.
J Comp Neurol. 2003 Dec 22;467(4):455-63.
 
Brandt MD, Jessberger S, Steiner B, Kronenberg G, Reuter K, Bick-Sander A, von der Behrens W, Kempermann G.
Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice.

Mol Cell Neurosci. 2003 Nov;24(3):603-13.