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.

Stem Cell Patch May Result In Improved Function Following Heart Attack

Researchers at the University of Cincinnati have discovered that applying a stem cell-infused patch in combination with the overexpression of a specific cell instruction molecule promoted the migration of cells to damaged heart tissue after a heart attack, which resulted in improved heart function in animal models.  They also found that heart function improved more so than when stem cells were directly injected in heart tissue—a therapy that is being studied elsewhere.

Yi-Gang Wang and his research group in the department of pathology and laboratory medicine found that when a tri-cell patch, made up of heart muscle cells (cardiomyocytes, which can restore heart contractility), blood vessel cells (endothelial cells which build new blood vessels) and embryonic fibroblasts (to provide support to the cell structure), was applied to the surface of the damaged area of the heart, better outcomes in overall heart function resulted.

Following heart attacks, the heart tissue becomes damaged and scarred.,  Heart muscle cells die and the pumping function of the heart is reduced.  While therapies exist, other researchers are examining stem cells injections directly into damaged heart muscle to see if contractile function can be restored.

This stem cell-based study differed other studies in that Wang’s s group wanted to determine if overexpression of a small RNA called miR-29 could enhance the effectiveness of an implanted cell patch.  The strategy behind overproducing this gene was to reduce barriers between cells in the infarcted area.  miR-29 is a small RNA molecule that is made in increased quantities once the heart undergoes a heart attack, and it seems to be involved in the scarring reaction that occurs after a heart attack.  Overexpression of miR-29 should lead to enhanced regeneration of heart tissues and restoration of heart function after a heart attack.

Researchers first generated cardiac progenitor cells—cells that can become various cardiac tissue cell types—from induced pluripotent stem cells (iPSCs).  These stem cells can differentiate into any type of cell in the body and are artificially derived from common body cells and are induced from a forced expression of several desired genes.

The iPSCs were then labeled with green fluorescent protein (GFP) and firefly luciferase (a glowing laboratory reagent) to help trace cell migration and proliferation into the animal’s system.

Researchers injected either the virus-mediated miR29b or a control material into the heart of the animal model and then experimentally induced a heart attack.  Wang said, “These models allowed us to determine the possible benefits of miR29b and outcomes observed in two different control groups.”

Three days following the heart attack, researchers placed a cell patch on the damaged region and measured the expression of cardiac-related genes, collagen levels in the damaged tissue and scar formation-related signaling pathways.  Collagen is the main component in scars and heart muscle scars that fill in heart tissue after heart attacks are no different.

One month after the cell patch implantation, echocardiograms were performed to evaluate heart function.  Cells mobilized into the infarcted region of the heart.  Analysis of these hearts by imaging determined the number of GFP-containing cells and the number of cells expressing firefly luciferase.  The researchers found the number of GFP cells, bio-luminescence signals and heart function as a whole significantly increased in animals with cells that overexpressed miR-29b and were treated with the tri-cell patch.

According to Wang:  “These findings show that an overexpression [sic] of miR-29 results in heart tissue changes that favor enhanced mobilization of desired cell types into infarct regions after heart attack, leading to improved heart function.  Hopefully, one day such treatments will restore cardiac function in patients who have experienced a heart attack, leading to a longer and better quality of life.”