May 15, 2014
A Fetal Enzyme Helps Stem Cells Recover From Limb Injuries
April Flowers for redOrbit.com - Your Universe Online
Nearly two million Americans a year suffer from ischemia reperfusion injuries. A wide variety of scenarios can be caused by these injuries that result in restricted blood flow—from traumatic limb injuries, to heart attacks, to donor organs. Restoring the blood flow to an injured leg, for example, seems like it would be a good idea. A new study from Georgia Regents University, however, suggests that restoring the flow could cause additional damage that actually hinders recovery.
Rather than promoting recovery, restoring blood flow actually heightens inflammation and cell death for many of these patients.
"Think about trying to hold onto a nuclear power plant after you unplug the electricity and cannot pump water to cool it down," said Dr. Jack Yu, Chief of MCG's Section of Plastic and Reconstructive Surgery. "All kinds of bad things start happening."
Yu collaborated with Dr. Babak Baban, immunologist at the Medical College of Georgia and College of Dental Medicine at Georgia Regents University. Their study, published in PLOS ONE, reveals that one way stem cell therapy appears to intervene is with the help of an enzyme also used by a fetus to escape rejection by the mother's immune system.
Baban notes that previous studies have found a correlation between stem cells and recovery. The stem cells both enable new blood vessel growth and by turning down the now-severe inflammation. The new findings reveal that ndoleomine 2,3 dioxygenase, or IDO, widely known to dampen the immune response and create tolerance, plays an important role in regulating inflammation in that scenario. IDO is expressed by stem cells and numerous other cell types.
Stem cell efficiency was boosted by approximately one-third when tested on animal models comparing the therapy in normal mice versus mice missing IDO. Decreased expression of inflammatory markers, swelling and cell death were all observed. These are all associated with shorter, improved recoveries.
"We don't want to turn off the immune system, we want to turn it back to normal," Baban said.
Even a brief period of inadequate blood flow, and the resulting lack of nutrients, can start problems that result in the rapid accumulation of destructive acidic metabolites, free radicals, and damage to cell structures. Mitochondria, which are the cells' power plants, should be producing the energy source ATP. Instead, they quickly become fat, leaky and dysfunctional in this situation.
"The mitochondria are sick; they are very, very sick," Yu said. Enormous additional stress is added to these sick powerhouses when blood flow is restored.
"They start to leak things that should not be outside the mitochondria," he said. Cells quickly give up without a source of adequate energy and leaky powerhouses. Inflammation is part of the normal healing process that escalates to help clean up the injury. In this case, however, it makes the problem worse.
The researchers focused their studies on limb injuries, but their findings should translate to any number of scenarios resulting in reperfusion injury. Yu notes that he has seen free flaps, where tissue is moved from one area of the body to another to cover a burn or rebuild a breast, start dying from ischemia reperfusion injury in just two hours.
"It cuts across many, many individual disease conditions," Yu said. To avoid reperfusion trauma, transplant centers are experimenting with pulsing donor organs.
The team plans to continue their studies by seeing if "more is better"—in other words, giving more stem cells, as well as IDO enhancing drugs. This will include incubating stem cells with IDO. During this study, only one dose was given.
Stem cell therapy isn't currently in use for aiding in the recovery of limb injuries, but it is being clinically studied to aid stroke and heart attack recovery at MCG and other centers. The best treatment currently available for reperfusion injuries is to restore blood flow and give broad-spectrum antibiotics.
"Sometimes it works, sometimes it doesn't," Yu said. "That is why this kind of pharmacologic intervention could be very, very important."