Inst. of Cell Biology - Institute Associated Research Group Stem Cell Biology And Regeneration
In the group stem cell biology & regeneration we investigate the mechanisms of proliferation and differentiation of adult neural stem cells. In particular we are interested in the question how the asymmetric cell division of these cells work. We investigate how the grade of differentiation of a cell is determined and how Neuroinflammation affects neural stem cells. Further on we try to find ways to reprogram differentiated cells back into stem cells. The overall aim of our work is to make endogenously present adult neural stem cells applicable for therapeutic approaches aiming for the replacement of neurons that are lost during neurodegenerative diseases (e.g. Parkinson’s disease)
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ZMBE, Inst. f. Cell Biology
Group Stem Cell Biology & Regeneration
Dr. Jens C. Schwamborn
E-Mail: jschwamb at uni-muenster.de
The group is participating in the following programs:
The adult mammalian central nervous system (CNS) has little capacity for regeneration after injury and disease. However, stem cells with the potential to proliferate and to differentiate into neurons are now known to exist throughout the CNS of all adult mammals, including humans. Under homeostatic conditions these new neurons are dedicated for the olfactory bulb and the dentate gyrus. Nevertheless in principal it is conceivable that neurons that are lost during neurodegenerative diseases (like Parkinson’s disease or Alzheimer’s disease) could be replaced by new neurons. These newborn neurons could be produced by the endogenously present adult neural stem cells. We investigate the mechanisms of adult neurogenesis and the effect of neuroinflammation on adult neural stem cells. The overall aim of our work is to make endogenously present adult neural stem cells applicable for therapeutic approaches aiming for the replacement of neurons that are lost during neurodegenerative diseases (e.g. Parkinson’s disease)
Adult neural stem cells & neurogenesis
The defining feature of stem cells is their capability to produce on the one hand more of themselves (self renewal) and on the other hand to produce more differentiated progeny. The production of new neurons by neural stem cells (so called neurogenesis) is not only happening during brain development but can be observed continuously also in the adult brain. Under homeostatic conditions neurogenesis is mainly occurring in two distinct regions of the adult brain, these are the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus.
Fig. 1: In the adult brain neural stem cells are restricted to the dentate gyrus and the subventricular zone (SVZ). Three cell types can be identified in the SVZ, these are adult neural stem cells (B-cells), transient amplifying cells (C-cells) and neuroblasts (A-cells). We investigate wheter these adult neural stem cells divide with an intrinsic asymmetry, thus we ask whether factors exist that are just inherited by only one of the two daughter cells of such a division.
Currently the mechanisms of asymmetric cell division and differentiation of adult neural stem cells and their progeny are poorly described. It is our aim to understand these mechanisms in detail and to use this knowledge to make adult neural stem cells applicable to replace neurons that are lost during neurodegenerative diseases. In particular we are focusing on the mechanisms of asymmetric cell divisions. We aim to identify and characterize the involved proteins and miRNAs. As a disease model for neurodegeneration we use Parkinson’s disease.
Fig. 2: Immunofluorescence pictures showing the two neurogenic regions of the adult brain. (A) Dentate gyrus of the Hippocampus; Yellow: Stem Cell and Astrocyte marker GFAP; Blue: DNA. (B) Subventricular zone; Green: Stem Cell and Astrocyte marker GFAP, Red: Marker for the apical membrane of ependymal cells; Blue: DNA.
Fig. 3 An asymmetrically dividing neural stem cell is shown. The cell is in mitosis (condensed DNA is shown in blue) and a cell fate determinant (in this particular case the protein TRIM32, shown in green) is enriched on just one pole of the dividing cell.
Neurodegenerative diseases are often associated with inflammation. We are interested in the question how inflammatory reactions affect neural stem cells. Do they have an impact on the capabilities of adult neural stem cells to proliferate, differentiate and migrate? In particular we are interested in the function of the NF-κB pathway during Neuroinflammation. Furthermore we use advanced imaging technologies (e.g Small Animal Positron Emission Tomography) to image degenerative processes and inflammation in mouse models for Parkinson’s disease (Fig. 4).
Fig. 4: PET system for small animals under operation.
Reprogramming into neural stem cells
Recently it has been show that somatic cells (e.g. fibroblasts) can be reprogrammed into embryonic stem cells (ES-Cells). This raises the question whether also a reprogramming into adult tissue specific stem cells is possible. We aim to reprogram adult postmitotic cells back into neural stem cells; ideally we would like to become able to perform such a reprogramming under in vivo conditions. Such an approach could have an enormous therapeutical potential.
Fig. 5: Neural stem cells in culture are shown. (A) Phase contrast image of freshly isolated neural stem cells that grow in as spheres (neurosphere culture). (B) A homogenous two dimensional culture of neural stem cells: Green: Stem cell marker Nestin; Red: Proliferation marker P-H3; Blue: DNA. (C) Differentiation of neural stem cells into neurons at the outer edge of a neurosphere. Green: Neuronal fate determinant; Red: Neuronal marker TuJ1, Blue: DNA.
Dr. Jens C. Schwamborn