Immune cells used to help muscle tissue heal in lab

- By tapping into the immune system, researchers have developed a way to help adult muscle tissue heal by regenerating in the lab, according to a study of mice.

Biomedical engineers at Duke University believe engineered tissue grafts can better survive in future cell therapy applications, offering ways to treat degenerative muscle diseases. The findings were published Monday in the journal Nature Biomedical Engineering.

Lab-made adult muscle tissues do not have the same regenerative potential as newborn tissue, but many degenerative muscle diseases do not appear until adulthood.

"I spent a year exploring methods to engineer muscle tissues from adult rat samples that would self-heal after injury," researcher Dr. Mark Juhas, a former Duke doctoral student, said in a press release. "Adding various drugs and growth factors known to help muscle repair had little effect, so I started to consider adding a supporting cell population that could react to injury and stimulate muscle regeneration. That's how I came up with macrophages, immune cells required for muscle's ability to self-repair in our bodies."

Juhas is part of the lab of Nenad Bursac, a professor of biomedical engineering at Duke who debuted the world's first self-healing, lab-grown skeletal muscle in 2014. The muscle healed itself inside the laboratory and an animal.

They took samples of muscle from rats just two days old, removed the cells and "planted" them into a lab-made environment perfectly tailored to help them grow.

Niches for muscle stem cells, known as satellite cells, activated upon injury and aided the regeneration process.

Macrophages, which are translated from Greek as "big eaters," are white blood cells in the body's immune system that engulf and digest cellular debris, pathogens and anything else they don't think should be hanging around. In addition they secrete factors that support tissue survival and repair.

After a muscle injury, a class of macrophages increases inflammation and stimulates other parts of the immune system. One of the cells recruited is a second kind of macrophage, dubbed M2, that decreases inflammation and encourages tissue repair.

"When we damaged the adult-derived engineered muscle with a toxin, we saw no functional recovery and muscle fibers would not build back," Bursac said. "But after we added the macrophages in the muscle, we had a wow moment. The muscle grew back over 15 days and contracted almost like it did before injury. It was really remarkable."

The researchers believe the macrophages act to protect damaged muscle cells from apoptosis, which is the process of programmed cell death. Although newborn muscle cells naturally resist stopping the process, adult muscle cells need the macrophages. These surviving muscle fibers help muscle stem cells latch onto them and perform their regenerative duties.

"We believe that the macrophages in our engineered muscle system may behave more like the muscle-resident macrophages people are born with," Bursac said. "We are currently working to understand if this is indeed the case. One could then envision 'training' macrophages to be better healers in a system like ours or augmenting them by genetic modifications and then implanting them into damaged sites in patients."

This means that adult tissues can be as effective as fetal and newborn tissues in healing.

"Building a platform to test these results in engineered human tissues is a clear next step," Bursac said. "We hope that our approach of supplementing lab-grown muscles with immune system cells will prove to be a general strategy to augment survival and function of other lab-grown tissues in future regeneration therapies."
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