The Protein Ephrin Herds Muscle Stem Cells to Form Adult Muscle

Satellite cells are dormant stem cells in skeletal muscles that come alive when the muscle is damaged. Do satellite cells from distant sites converge upon damaged muscle sites, or does muscle repair depend on locally available satellite cells? Also, if muscle is repaired by local and more far-flung satellite cell populations, what is the signal that wakes satellite cells from their slumbers and brings to them to damaged area? Furthermore, can we manipulate these signals to bring satellite cells to muscles that need healing but are not damaged in a manner that satellite cells can effectively detect? Knowing the answers to questions like these could potentially allow researchers to treat muscle disorders such as muscular dystrophy, in which the muscle is easily damaged and the patient’s satellite cells have lost the ability to repair.

Researchers from the Cornelison lab at the University of Missouri, Columbia have used time-lapse microscopy to follow precisely the movement of the satellite cells over various substrates that were painted onto glass slides. By watching satellite cells move over the stripes of substrates, Cornelison and her colleagues discovered that a protein called “ephrin” is a repulsive signal for satellite cells. When satellite cells that were placed on glass slides encountered striped of ephrin protein, those cells would touch the ephrin stripes and immediately turn around and travel in a new direction.

The significance of this finding is not lost on Cornelison, who commented: “There is currently no effective satellite cell-based therapy for muscular dystrophy in humans. One problem with current treatments is that it requires 100 stem cell injections per square centimeter, and up to 4,000 injections in a single muscle for the patient, because the stem cells don’t seem to be able to spread out very far. If we can learn how normal, healthy satellite cells are able to travel around in the muscles, clinical researchers might use that information to change how injected cells act and improve the efficiency of the treatment.”

How is ephrin directing satellite cell migration? Cornelison hypothesize: “Because the long, parallel muscle fibers carry these ephrin proteins on their surface, ephrin might be helping satellite cells move in a straighter line towards a distant ‘mayday’ signal.”

Further work on satellite muscle cells by Cornelison’s lab showed that when they gave cultured satellite cells signals to differentiate and fuse to form muscle fibers in culture, they could simultaneously use painted striped of ephrin proteins to herd the cells into parallel arrays. This is a striking find because muscle fibers always form parallel arrays in living organisms, but no one has been able to persuade muscle fibers to do this very thing in culture. Thus, it is entirely possible that ephrins are one of the major molecules that regulate several of the different steps required to move a population of stem cells that are spread out all over the muscle, to an organized, properly patterned new muscle fiber.

“We are really excited about the potential of these findings to explain a lot of things that were puzzling about the way satellite cells behave in healthy muscle, compared to a muscular dystrophy patient’s own cells, or cells that have been injected therapeutically,” Cornelison said. “If we’re really lucky, we could find something that could make a difference in these kids’ lives, and that’s what we want the most.”