Wounded cells

A cross-section of traumatically injured muscle tissue containing progenitor cells (green). Muscle fibers (dark) do not contain nuclei (blue).

The injured soldier, a patient at Walter Reed Army Medical Center in Washington DC, was unforgettable. “He was a special forces guy, in the middle of a firefight,” his physician Leon Nesti recalls. “His leg was blown off above the knee. In the middle of this firefight, he picked up his leg and used it to stabilize his weapon, and kept firing at the enemy.”

When the soldier arrived at Walter Reed about 4 years ago, Nesti says they had to take him to the operating room every couple of days to clean the wounds and remove damaged muscle tissue. Finally, he was fitted for a prosthetic.

But about a month later, his prosthetic became painful. The soft tissue that attached to the device had turned hard and stiff....

It was a condition Nesti had been seeing frequently in injured soldiers from the wars in Iraq (where this soldier had been based) and Afghanistan, and he wondered what was happening in their bodies. The disorder occurs in the civilian population as well, sometimes in victims of car crashes and even some athletic injuries, but its etiology and mechanism are poorly understood. And, it was occurring in these soldiers at rates previously unheard of—as many as 65 percent of amputees were developing heterotopic ossification. Previous research has documented heterotopic ossification in only one-quarter of patients who had abdominal surgery or hip replacement. (J Comput Assist Tomogr., 32:872–76, 2008; J Arthroplasty, 2009 e-pub June 2.)

Nesti wondered if there was a clue in the discarded tissue surrounding the injury that could shed light on why their tissue ossified so frequently. To take a closer look at the soldiers’ tissue, Nesti contacted Rocky Tuan, now the director of the center for cellular and molecular engineering at the University of Pittsburgh, and Nesti’s postdoc supervisor.

Soldiers’ wounded tissue was ossifying—why?

Along with other members of Tuan’s lab at the National Institutes for Health, they analyzed samples of the tissue extracted from the wounded soldiers during surgery. What they found shocked them. The traumatized muscle tissue was chock full of stem cells—nearly 4,000 times the density found in bone marrow and considerably higher than what has ever been found in normal muscle tissue (J Bone Joint Surg Am., 90:2390–98, 2008).

Further analysis revealed that the stem cells were already being pushed to specify into a certain cell type, expressing more osteogenic and nerve-generating factors. (J Orthop Res. 2009 Jun 10, e-pub ahead of print).

Tuan and Nesti think that the proliferation of progenitor cells following a serious injury is an overzealous healing response, which leads to heterotopic ossification. “It makes sense, that if the body is injured it sends off signals to recruit stem cells to the site of the injury to speed up the healing process,” says Nesti. But, why these cells seem to be differentiating into bone as opposed to muscle is still a mystery.

George Muschler, a biomedical engineer at the Cleveland Clinic, agrees that the soldiers’ heterotopic bone formation likely traces back to these progenitor cells, perhaps to issues during their recruitment to the site of the injury and differentiation. These excess progenitor cells are also probably a “central element in wound repair and tissue regeneration,” he adds.

Robert Pignolo, director of the Ralston-Penn Clinic for Osteoporosis and Related Bone Disorders in Philadelphia, also agrees that the cells are likely behind the bone formation, but cautions that stem cells often behave differently in culture than live tissue—so just because they exhibit osteogenic properties in vitro, does not mean that they will form bone when implanted in a living organism.

Nesti and Tuan are also evaluating the progenitor cells’ therapeutic potential, particularly for peripheral nerve regeneration (J Tissue Eng Regen Med., 3:129–38, 2009). The cells secrete nerve-inducing factors, says Tuan, and recent unpublished experiments by him and Nesti have suggested that they can speed up the process of nerve regeneration.

The fact that much of this research was made possible because of the wars is not lost on either Tuan or Nesti. “It’s one of the few positive outcomes of war, I guess,” says Tuan.

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