A new strategy for spinal cord injury


Researchers at Ohio State University are trying to determine how to improve healing after spinal cord injuries by simultaneously stop damage and promote neuron growth with a single, targeted signal. After the initial insult to the spinal cord, further damage is continued by cells called macrophages, a type of white blood cell found in injured tissue. After spinal cord injury, macrophages travel to the injury site from at least three known locations in the body as part of an intense inflammatory response, and after several days, these cells promote inflammation and toxicity, which exacerbates effects of the original injury. But these same cells might also offer hope for restoration of function in people with injured spinal cords.
In previous research, scientists determined that macrophages receive signals at the site of a spinal cord injury that cause them to both promote the growth of axons (those extensions that allow for communication among nerve cells), and cause tissue damage. This new study suggests that there could be a way to manipulate these signals to silence the damaging effects while enhancing the repair function. John Gensel, a postdoctoral researcher at Ohio State University and lead author of the study, said, “We know a single population of macrophages has both capabilities, but we’ve also found that there are some specific receptors we can target that reduce the pathological potential of macrophages while retaining their regenerative characteristics.”
The goal of this research was to manipulate the immune response after spinal cord injury. An estimated 1.3 million people in the United States are living with a spinal cord injury, and they experience paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain. By using synthetic molecules to stimulate macrophages, the researchers previously showed that multiple receptors on these cells were involved in their activation, and that these receptors dictate how the macrophages behave. If more than one receptor is stimulated, the macrophage has the potential to either kill a nerve cell, stimulate it to grow, or both.
Director of Ohio State’s Center for Brain and Spinal Cord Repair, Phillip Popovich, who was also a coauthor of this study,  noted:  “What we’re trying to do is split the activation switch, so there could be two switches and you can keep one off and turn the other one on. We think we have learned how to do that, at least with regard to one signaling pathway.” There are actually thousands of potential activators present in these complex injuries, and by exploring signals that control the cells’ behavior at a specific time point in the injury, Gensel and his colleagues are getting closer to zeroing in on which receptor on the cell surface to target to promote repair.
Two receptors, known as TLR-2 and dectin-1, are present on the surfaces of macrophages and when both receptors are activated, the macrophages simultaneously perform damaging and reparative functions in the spinal cord. But when only the TLR-2 receptor was stimulated, the cells retained their regenerative effect without creating a toxic environment. In contrast, when only dectin-1 was stimulated, the macrophages killed the nerve cells. An experimental compound used in the study was able to activate the TLR-2 receptor alone in cell cultures, which enhanced the growth of axons without causing cell death. When introduced to the spinal cords of rats, the compound caused inflammation, but little tissue damage.
“Now we have to go into the cell to figure out what part of that signaling process we can manipulate and if that manipulation can stop the toxicity,” Gensel said. Ultimately, the scientists hope to identify a precise target for drug therapy that could alter the immune response after the devastating effects of the injury and tip the balance of macrophage activity toward nerve cell repair.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).