Experimental Neuroregeneration
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Institute of Experimental Neuroregeneration

Director: Univ.-Prof. Dr. Sébastien Couillard-Després



The Research Institute of Experimental Neuroregeneration was founded in August 2013 as part of the Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS) at Paracelsus Medical Private University.

The objective of the research work is the restoration of the functions which have been lost as a result of traumas or diseases of the central nervous system. In particular, the restoration of the motor and sensoric functions after an injury of the spinal cord.

In the central nervous system itself, regenerative capabilities have already been proven. However, they are not sufficient to significantly restore the lost functions after an injury of the spinal cord. Therefore, we perform research on the development of new substances and therapies which increase the intrinsical regenerative capabilities of the central nervous system. Also the use of stem cells and precursor cells of the own body within the framework of the regenerative therapies is increasingly researched. These cells are in a position to replace the lost neurons and glial cells and can, in addition, convert the lesion environment into a pro-regenerative environment.


The focus points of our research:

  • Therapies with adult stem cells
  • Pre-clinical models of the transverse spinal cord syndrome
  • Stimulation of the endogenous neurogenesis and gliogenesis

Projects

Pre-clinical models of injuries of the spinal cord and therapy development

Damages of the spinal cord represent grave injuries which in most cases have life-long consequences for the respective affected persons.

The pathophysiology of the transverse spinal cord syndrome can be seen as a two-part event. After the initial trauma per se, which leads to tissue laceration, petechial bleeding and finally to the cell death, the internal bleeding and the degradation products of the cells within the injured spinal cord cause a number of secondary damages, which include ischemia, excitotoxicity, forming of oedemas and strong inflammatory component. After a certain amount of time, a scar with pseudo-cyst is formed – depending on the size of the injury. This process helps, on the one hand, to contain the pathological process and preven the further spreading of the problem but, on the other hand, it makes a potential neuro-regeneration difficult.

In various pre-clinical models of spinal cord injuries, we research the effect of potential neuro-protective and neuro-regenerative therapies. Here belong, on the one hand, the administration of various flavonoids such as the prenylflavonoid ENDF1, as well as cell-based therapies. After the respective therapy, the locomotor and sensoric progress is evaluated, as well as the effect on inflammatory processes, the formation of scars and the axonal regeneration are studied.


Immature nerve cells in the central nervous system of adult persons: alternative form of neurogenesis in adult persons

The neurogenesis in adult persons, the new formation of nerve cells, is observed in the brain of adult mammals in two neurogeneous niches, the gyrus dentatus in the hippocampus and the subventricular zone along the lateral ventricle. In addition, neuronal cells of the precursor type were proven in the further regions of the brain. For example, in the cortex piriforms, a region which, among other things, participates in the processing of odors, cells were found, which are the same as immature neurons. Until now it is only known that these cells develop before birth and remain dormant in immature state. In older individuals, the number of these sells decreases significantly. The fate of these cells, either cell death or maturing into another cell type, could not be determined until now due lack of adequate methods. For this purpose, we have recently generated a transgenic model (DCX-CreERT2/Flox-EGFP), in which doublecortin-expressed cells could be marked permanently with a green referent by the addition of tamoxifen. The purpose of this project is to analyse these immature cells – their ultrastructure, their electro-physiological activity, their fate, their origin, their effect on the behaviour and their existence in humans and animals.

In the analysis of the cortex piriforms we could show that the previously immature cells do not die but mature locally to glutamatergic pyramidal cells. Furthermore, it could be shown that the cells have matured both morphologically and functionally. The immature neurons of the cortex piriforms and the cells, into which they can develop, can be studied electro-physiologically in acute-type cut with the help of a transgenic model. During the electro-physiological measurements, the cells are filled with biocytin. In this way, the identity of the studied cells can be clearly determined and described further with the help of immunhisto-chemistry and electron microscopy. In order to identify these cells in various species, including man, we also use electron microscopy. Consequently, this project will show whether the neurogenic capacity of the human brain has been seriously underestimated and whether there is a limited reservoir of immature nerve cells, which build additional new neurons and thus can keep the ageing brain in a more plastic condition as it was accepted until now.


Induced oligodendrogenesis of adult neural stem cells by means of mesenchymal stem sells - researching the signal path

The stem cells exist in grown-up organisms in different tissues and can rebuild injured or destroyed tissues. Well-known examples are the mesenchymale stem cells (MSCs) which are present in the bone marrow. However, the central nervous system (ZNS), too,contains a stem cell pool, the so-called neural stem cells (NSCs), which can be differentiated in the astrogenic, oligodendrogenic or neuronal line. Demyelinating diseases such as, for example, multiple sclerosis, lead to damage of the myelin layer, which is built by the oligodendrocytes, and further on to a loss of the nerve function. The own potential of the regeneration decreases with the duration of the disease and the age of the affected person. Effective therapies, which stop the process of the disease or improve the regeneration, do not exist at present.

It could be shown in in-vitro experiments that soluble factors, which are secreted by the MSCs, can make the NSCs to differentiate in oligodendroglial direction. However, the molecular mechanisms and the signal-transduction paths, through which this effect takes place, are not known at present. Our goal is to find out through which signal-transduction path the oligodendrogenesis, which is induced by the MSCs, is mediated, in order to find a possible therapy for improving the regeneration. With the help of NSC cultures, various signal paths are tested in vitro and are eliminated by means of specific inhibitors. In this way it is researched which signal path has a direct effect on the MSCs-induced oligodendrogenesis. Through the knowledge of a main signal path in the oligodendrogenesis, new phrarmacological applications for the remyelinisation could be developed.


Flavonoids: Neuro-regenerative substances for damaged nervous system

The flavonoids, a class of secondary plant metabolites, already show many positive effects on the human organism. Consequently, nutrition rich in flavonoids reduced the loss of memory in Morbus Alzheimer's. In addition, certain flavonoids had antidepressive and anxiolytic effects in studies on animals. Humulus lupulus L., generally known as common hop, is a plant which is very rich in flavonoids. In various in vitro experiments of our work group, we were able to prove an increased neuronal differentiation rate after the treatment of neural stem cell cultures with some of these flavonoids. In addition, some flavonoids have induced a strong growth and offshoots of neurites and they had a neuroprotective effect. On the basis of these results, the flavonoids are researched in vivo for their pharmacological effect and their area of application in the central nervous system is researched.

In our current projects, we occupy ourselves with the question about whether ENDF1 affects the neurite growth of neurons of the dorsal root ganglia as well as the complexity of these neurites. In the first experiments, we could determine that ENDF1 shows a positive effect on the growth of the neurites and eliminates fully or partially the growth-retarding effect of the various naturally existing inhibitors. The molecular mechanisms behind this effect are a central area of our research.

Team and contact

Univ.-Prof. Dr. Sebastien Couillard-Despres, Ph.D.
Institute of Experimental Neuroregeneration
Director

Phone: +43 662 2420-80830
Mobile: +43 699 14420058
Mail: s.couillard-despres@pmu.ac.at
Publications
Rosemarie Granig, MBA
Institute of Experimental Neuroregeneration
Assistant to the Director

Phone: +43 662 2420-80831
Mail: rosemarie.granig@pmu.ac.at
Dr. Bruno Benedetti, Ph.D.
Institute of Experimental Neuroregeneration
Senior Postdoc

Phone: +43662 2420-80835
Mail: bruno.benedetti@pmu.ac.at
Publications
Lara Sophie Bieler, BSc, MSc, Ph.D.
Institute of Experimental Neuroregeneration
Postdoc

Phone: +43 662 2420-80835
Mail: lara.bieler@pmu.ac.at
Publications
Ing.in Dominika Jakubec-Haščák, BSc
Institute of Experimental Neuroregeneration
Technical Assistant
Core Facility Preclinical Development Unit


Phone: +43 662 2420-80837
Mail: d.jakubec-hascak@pmu.ac.at
Publications
Ariane Benedetti
Institute of Experimental Neuroregeneration
Technical Assistant
Core Facility Preclinical Development Unit


Phone: +43 662 2420-80836
Mail: ariane.benedetti@pmu.ac.at
Publications
Teresa König, , BSc
Institute of Experimental Neuroregeneration
Master student

Mail: teresa.koenig@pmu.ac.at
Publications
Anna O`Sullivan, PhD
Institute for Experimental Neuroregeneration
Research Associate

Mail: a.osullivan@salk.at
Publications
Christian Grabner, BSc, MSc, MSc
Institute of Experimental Neuroregeneration

PhD student

Phone: +43 662 2420-80834
Mail: christian.grabner@pmu.ac.at
Publications
Ibrahim Khan, BSc, MSc
Institute of Experimental Neuroregeneration
PhD Student

Phone: +43 662 2420-80837
Mail: ibrahim.khan@pmu.ac.at
Moritz Brosch, BSc
Institute of Experimental Neuroregeneration
Master student

Phone: +43 662 2420-80837
Mail: moritz.brosch@pmu.ac.at
Fabian Johannes Blessing, BSc.
Institute of Experimental Neuroregeneration
Master student

Phone: +43 (0)662 2420-80837
Mail: fabian.blessing@pmu.ac.at