cortex

Project number:

801

Project title:

Characterization of adult spinal cord progenitor cells in the intact and injured spinal cord

Project supervisor:

Michaela Thallmair and Martin Schwab, Brain Research Institute, University of Zurich

Project description:

Understanding the basic mechanisms that regulate adult neural progenitor cell behavior is of great neurobiological interest, since elucidation of these basic questions is fundamental for developing strategies that aim to treat CNS injuries or diseases using neural stem cells.
The objective of this PhD thesis is to contribute to the characterization of how proliferation, migration, survival and differentiation in the intact and injured adult spinal cord are regulated.
Inflammation upon a CNS injury is a double-edged sword, on one hand inflammatory cells have been shown to direct proliferation, migration and differentiation of adult progenitor cells, but on the other hand some studies showed that inflammation decreases survival of progenitor cells and may enhance the production of astrocytes at the expense of other CNS cell types. One of the aims of this work is, thus, to determine the influence of inflammatory cells on adult spinal cord progenitor cells following a spinal cord injury.
The non-neurogenic character of the spinal cord and the limited differentiation into mature glial cells in spite of high proliferative activity after injury are considered two of the factors contributing to the poor regenerative capacity of the lesioned spinal cord. Currently it is not understood which factors in the mature spinal cord suppress neurogenesis and/or instruct gliogenesis. In addition, it is not known why only a subpopulation of proliferating progenitors is able to differentiate into a mature phenotype in the adult, injured spinal cord. To address these questions one approach in this PhD project is designed to determine whether formation of new motoneurons can be induced under specific conditions, i.e. following the rapid apoptotic cell death of motoneurons in the adult spinal cord.
Studies have shown that the majority of progenitor cells in the adult spinal cord become glial cells, however, only a subpopulation of progenitor cells matures to a glial cells following an injury. Since pilot experiments suggested that there may be two populations of progenitor cells in the adult spinal cord, one acting in the intact, one in the injured spinal cord, the third part of this PhD project aims to characterize progenitor cells in the intact and injured cord regarding their intrinsic properties using in vivo and in vitro approaches.

In summary, within this PhD project three main goals will be pursued:

1) Determine the influence of inflammatory cells on adult spinal cord progenitor cells following a spinal cord injury

2) Determine whether neurogenesis can be induced following apoptotic cell death in the normally non-neurogenic adult spinal cord

3) Determine whether there is more than one population of spinal cord progenitor cells in the adult spinal cord (intact vs. injured), and if so, how these cells differ regarding their intrinsic properties

Methods to be used:

spinal cord injury model: thoracic dorsal hemisection and/or cervical hemisection in mice and rats (goals 1 & 3)

bromodeoxyuridine labeling for proliferating cells (goals 1-3)

immunohistochemistry and immunocytochemistry to analyze proliferation, cell death, migration and fate decision of spinal cord progenitor cells in vivo and in vitro (goals 1-3)

injection of toxins that lead to cell suicide (goal 2)

use of a transgenic inducible mouse model to abolish the inflammatory response after a spinal cord injury (mouse will be provided by Prof. A. Aguzzi, Dept. of Pathology, University Hospital Zurich, goal 1)

FACS (fluorescent activated cell sorting) and Gene Chip analyses of isolated progenitor cells from intact and injured spinal cord (goal 3)

Retrograde fiber tracing (goal 2)

Possible cortex partners for rotation:

For this project, we see an added value in collaborating with the partners in Prague: the methods of in-vivo cell-tracking could also be applicable for all goals 1 – 3. Some of the key questions of the London group are also complementary to this project, namely the integration of neural stem cells into existing neural networks and the characterization of neuronal properties of stem cell lines together with the company Reneuron. The project will also profit from the work on spinal cord injury by Sten Grillner and his colleagues from Stockholm.