Loading...
Files
Date
Authors
Publisher
Philipps-Universität Marburg
Supervisors
Abstract
Parkinson's disease (PD) is caused by a progressive loss of dopaminergic
neurons in the substantia nigra pars compacta (SNpc), which results in
dopamine (DA) depletion in the brain of affected patients. Today's therapy
options are mostly symptomatic and limited to pharmacological replacement
therapy of DA. Because medication is associated with several side-effects and
efficacy of the treatment subsides with time, alternative therapy options are
studied since many years. Especially transplantation of endogenous and
exogenous dopaminergic stem cells as a possible cure for PD is increasingly
under investigation.
The adult mammalian brain contains only two regions that maintain the lifelong
capacity to generate new neurons, a process which is called neurogenesis. The
first region is the subgranular layer (SGZ) which is located in the dentate gyrus
of the hippocampus. The second region is the subventricular zone (SVZ)
adjacent to the walls of the lateral ventricles of the telencephalon. Neurons
deriving from neural stem cells (NSCs) of the SVZ migrate along the rostral
migratory stream (RMS) towards the olfactory bulb (BO). After reaching the BO
these neurons differentiate into mature interneurons before integrating into the
granular (GCL) or periglomerular cell layer (PGL). Approximately 40% of the
newly integrated neurons of the PGL show a dopaminergic phenotype.
The aim of the present study was to investigate the localization of the
dopaminergic NSCs in the SVZ-RMS-BO-system. It is of special interest to find
the exact position of these neurons because they could be used for
transplantation projects in clinical studies.
To elucidate this question we used a mouse model consisting of 11 animals and
implanted a physical barrier (PB) to mechanically interrupt the RMS. Depletion
of neural progenitors in the SVZ and RMS was achieved by a continuous
infusion of AraC (cytosine β-D-arabinofuranoside) administered for one week.
Subsequently newly proliferating neurons were labeled by BrdU (5-bromo-2'-
deoxyuridine), an analogue of thymidine. The experimental group consisted of 8
animals which were sacrificed 55 (n=4) and 105 days (n=4) after stopping the
AraC application. The three animals of the control group received neither a
surgery for PB implantation nor AraC treatment. They only obtained BrdU
injections and were sacrificed on day 105. For further analysis the mouse brains
were removed from the skull. The brain tissue was processed and
immunhistochemically stained.
The proper function of the PB, as required for the experiment, was confirmed by
investigation of the SVZ. As expected after depletion of the neuroblasts
neurogenesis was regenerating after treatment, which was confirmed by BrdU
immunostaining. Furthermore a distinct accumulation of neuroblasts in the SVZ
on the interrupted side indicated a proper function of the PB. Interestingly, the
BrdU staining of the BO on the interrupted side showed a significant reduction
of new born neurons in the GCL, but not in the PGL. This result clearly implies
that NSCs, which produce interneurons destined for the GCL are located in the
SVZ, whereas NSCs which provide interneurons for the PGL (including
dopaminergic interneurons) must be located in the RMS. With the help of a
BrdU/NeuN-double staining of the PGL it was confirmed that the cell type of the
new born cells were mainly neurons instead of reactive glial cells. Furthermore,
various stainings, especially the TH-staining of the PGL validated a constant
level of dopaminergic neurons.
To the best of our knowledge, this is the first work detecting dopaminergic stem
cells in the RMS of a mouse model by mechanical interruption of the RMS.
These findings are congruent with the results of different scientific groups and
support the hypothesis that the SVZ-RMS-BO system is a complex proliferative
zone. In addition, it becomes obvious that NSCs are an inhomogenous cell
population in which NSCs of distinct regions produce different subtypes of
neurons. This diverse character of NSCs is described as regionalization by
different authors.
Stem cell therapy of the central nervous system is a promising new approach
for the treatment of PD as well as for other neurodegenerative and
neurooncological diseases. Previously described sources of dopaminergic stem
cells comprise several disadvantages and clinical limitations. The extraction of
dopaminergic NSCs from the RMS could be a promising alternative to
overcome current objections. First preliminary studies on rodents and humans
were already successfully accomplished.
Review
Metadata
Contributors
Supervisor:
Dates
Created: 2020Issued: 2020-11-10Updated: 2020-11-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
mouse modelNeurogeneseMorbus ParkinsonMausmodelldopaminerge Stammzellenrostraler MigrationsstromParkinson's diseaserostral migratory streamolfactory bulbNeurogenesisolfaktorischer Bulbusdopaminergic stem cells
DDC-Numbers
610
show more
Rüschoff-Steiner, Corinna Heidi: Dopaminerge Stammzellen im rostralen Migrationsstrom der Maus. : Philipps-Universität Marburg 2020-11-10. DOI: https://doi.org/10.17192/z2020.0391.