Novel stem cell technology creates a
new cell for repairing spinal cord injuries
The researchers:
The lead research team in this work is Jeannette and Stephen Davies of Baylor College of Medicine, collaborating with Margot Mayer-Pröschel, Chris Pröschel and Mark Noble of University of Rochester Medical Center.
Background:
One of the remarkable features of the embryonic spinal cord that disappears during early development is a striking capacity to repair damage.
Unlike the adult central nervous system (brain and spinal cord), when nerve fibers are cut in the embryonic CNS, they are able to regenerate past the site of injury and re-establish connections. While no one knows why the developing brain and spinal cord are able to repair damage so effectively, one possibility lies in the reaction of support cells (called astrocytes) to injury.
Astrocytes are a major cell type in the brain and spinal cord and have many functions, including promotion of cell survival and support of nerve fibers (called axons). In the injured adult spinal cord, astrocytes are known to contribute to the formation of scar tissue that inhibits nerve fiber regeneration. However in the immature central nervous system, the immature astrocytes do not form inhibitory scar tissue and are thought to play a significant role in supporting axon regeneration and recovery. For many years there has therefore been a great deal of interest in using immature astrocytes to repair the injured adult central nervous system.
Embryonic astrocytes however are very difficult to obtain, particularly in numbers large enough to fill an adult spinal cord injury. Alternatively, although transplantation of neural stem cells into injury sites often results in these cells turning into astrocytes, it is thought that signals within the injury site turn (“differentiate”) the stem cells into more adult scar-like astrocytes that are poorly supportive of nerve fiber regeneration.
Research:
In the study from Davies et al., therefore the step was taken to first differentiate embryonic precursor cells into a specific type of immature astrocyte before transplanting them into a spinal cord injury. In other words, the researchers controlled which type of cell was formed, rather than letting this be controlled by signals within the injury site.
To generate cells more like the astrocytes of the embryonic spinal cord, the research team took advantage of the discovery of a cell thought to generate embryonic astrocytes during development of the spinal cord. These cells, first identified by co-author Dr. Margot Mayer-Pröschel (of the University of Rochester Medical Center) are called glial-restricted precursor (GRP) cells. The researchers made pure cultures of GRP cells from the embryonic rat spinal cord, grew them in large numbers in tissue culture, and then treated them with a protein thought to signal the embryonic spinal cord to make astrocytes.
Pre-differentiating the GRP cells into embryonic astrocytes in culture before transplanting them into experimental spinal cord injuries promoted a level of repair that surpasses that previously obtained with any other form of cell transplantation. More than 60% of sensory nerve fibers within the damaged spinal cord extended into the injury site, and over two-thirds of these nerve fibers [Note: i.e. two thirds of 60%] grew all the way through the injury site and back into their former pathway, in just 8 days. The transplanted cells also suppressed the normal scarring reaction in the nervous system for several days. Another important effect of the transplanted cells was to cause an alignment of damaged tissue so that instead of forming a chaotic scar, adult astrocytes at the injury site had aligned with the normal orientation of axons within spinal cord pathways. Furthermore, neurons in the brain that normally degenerate when their nerve fibers are severed in the spinal cord, were rescued by interactions of their cut nerve fibers with the precursor-derived astrocytes transplanted into spinal cord injuries.
Importantly, in a sensitive test of limb placement during walking, rats that received the astrocyte transplants recovered and were able to walk normally within two weeks, whereas the other spinal injured rats did not recover at all and still had difficulties with walking four weeks after the surgery.
What was particularly striking about these studies was that transplantation of the precursor cells themselves did not provide any benefit at all, thus challenging the idea that transplantation of stem cells or precursor cells is the optimal way to promote tissue repair. Instead, the results of this study demonstrate that the injured adult spinal cord may not provide the signals necessary to turn transplanted stem cells into the best cells for repairing the injured nervous system.
These studies take an important step in developing the use of stem or precursor cell technology for tissue repair in the injured adult central nervous system. While many research groups have shown that transplantation of a variety of stem cells and peripheral nervous cells can provide varying degrees of benefit in experimental models of spinal cord injury, functional repair has usually required combining cell transplantation with multiple other therapies. The results of this study, in contrast, show that selection of the right type of central nervous system cell for repairing the central nervous system can provide extensive benefits without additional therapies.
When does the work transition to humans:
All of the scientists of this research team are members of the New York State Center of Research Excellence in Spinal Cord Injury, a group of 18 laboratories in New York State and elsewhere. This Center was funded in response to an application authored by Drs. Rajiv Ratan (Director of the Burke/Cornell Medical Research Institute) and Mark Noble (Professor of Genetics, Neurobiology and Anatomy, URMC). The goal of this center is to develop rational combinatorial approaches to the repair of SCI, and includes expertise in areas of drug discovery, spinal cord injury, stem cell research, regeneration biology, robotics, physical therapy and clinical trials. This work will now begin the process of discovery required to move through pre-clinical investigations and on to clinical trials.
This project was supported by grants from the Christopher Reeve Foundation, the New York State Spinal Injury Research Program and the National Institutes of Health.
PPA Funded Research 
