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Spinal cord injury repair

Project overview

This work is a collaborative effort with our colleagues Drs. Chris Pröschel and Mark Noble and with Stephen and Jeanette Davies at the University of Colorado.

One of the hallmarks of any spinal cord injury (SCI) is the massive cell destruction that follows an initial phase of inflammation. In order to replace the lost cells, or allow surviving cells to reestablish functional connections, it is critical to first generate a permissive environment at the injury site that allows normal healthy cells to grow and thrive. Many investigators have pursued cell-based transplantation strategies with an array of varies central nervous system and peripheral nervous system derived cells that would allow endogenous neurons to send out axons across the injury site. Although transplants of some cell types have provided more benefit than others, in general there was a lack of significant axon regeneration beyond sites of injury. In order to understand why so many cell transplants underperformed we approached this issue from a different angle and first focused on generating a normal glial environment that is necessary for neuronal function. Our initial experiments in which we transplanted astrocytes that were derived from embryonic spinal cord glial restricted precursor cells (sGRPs) proved to be extremely successful. We transplanted astrocytes that were generated by exposing cultures of purified sGRP cells to bone morphogenetic protein-4 (BMP) (sGDABMPs), a signaling molecule that is thought to play an important role in promoting astrocyte generation in the developing spinal cord into a dorsal transection models of SCI. Transplantation of sGDABMP, but not of sGRP cells, promotes extensive regeneration of dorsal column axons in the transected spinal cord, including regeneration of a large proportion of axons through the lesion site and back into normal tissue on the other side of the injury. The extensive regeneration of dorsal column axons in the transected spinal cord is associated with complete functional recovery. In contrast, when we generate the astrocytes using the different signal CNTF, the transplanted astrocytes failed to lead to function recovery and in addition, generate a neuropathic pain syndrome. These experiments showed that it is critical to use the right cells in the right context to generate desirable outcomes (see Davies et al, 2006 and 2008 J Biol).
We are now in the process of extending these important finding by devising a rational approach to identify the optimal cell source and cell population for SCI repair and to extend the behavioral outcome to the characterization of the graft cells and the injury site in respect to cell death, inflammation and cell division. One of our major goals is to identify a number of factors that can be tested in vitro which would allow us to make predictions of the efficacy of a cell in vivo. We also are working to determine whether it is necessary for a function recovery to transplant cells of a specific origin (ie spinal cord) or specific age and whether pre-differentiated into specific astrocytes is a necessary step to generate positive outcomes after transplantation.

Contact

Margot Mayer-Pröschel
University of Rochester
Box 633
601 Elmwood Ave.
Rochester, NY 14642
Office: MRB 2-9627
+1-585-273-1449
margot_mayer-proschel@urmc.
rochester.edu

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