Revisiting Satellite Cells

by Margaret Wahl on November 1, 2005 - 9:51am

QUEST Vol. 12, No. 6

Ottawa Health Research Institute

Decoding pathways of muscle-cell development and repair

Laboratory experiments

Michael Rudnicki, Ph.D.
Michael Rudnicki, Ph.D.

"I think that when the results of those first experiments from the 1990s came in — that myoblast transplants don’t work — alarm bells rang,” says Michael Rudnicki, an MDA research grantee at the Ottawa Health Research Institute, where he heads the Program in Molecular Medicine.

In 1988, after earning a doctoral degree in biology at the University of Ottawa, Rudnicki went to the Massachusetts Institute of Technology’s Whitehead Institute in Cambridge for postdoctoral studies.

There he trained with famed molecular geneticist Rudolf Jaenisch, who, in the 1970s, had been among the first scientists to insert DNA into mouse embryos and breed mice with conditions mimicking human disorders.

Rudnicki joined this effort, producing and analyzing mice with genetic mutations. He concentrated on figuring out the function of the myoD proteins, which push undifferentiated cells toward becoming muscle.

In Rudnicki’s view, a principal reason for the failure of most of the myoblasts to survive and join the recipients’ muscle fibers is the nature of the cells that were chosen.

“The state of the art for satellite cell biology was really descriptive histology [study of tissues],” he says. “There were a few exceptions, cell biologists working in the area. But they were primarily not involved with genetics or molecular mechanisms.

“It was thought that myoblasts were the same as satellite cells,” Rudnicki says of the early 1990s, “and that is absolutely incorrect.”

A muscle satellite cell, Rudnicki says, “is defined by its anatomical location. It’s beneath the basal lamina [a tough sheath surrounding each fiber], closely nested in a cleft against a muscle fiber. Within that population, some portion of the cells may have more robust self-renewal and expansion capacity than others, but satellite cells clearly are upstream [earlier in their development] from myoblasts.”

When a satellite cell becomes activated (as it does when fiber repairs are called for), Rudnicki says, it starts making proteins called myf5 and myoD. At that point, it becomes a true muscle precursor cell. “Then, if we put that into a culture dish, we get what we would call a primary myoblast,” he says.

Once a cell has reached that stage, it can’t go back to being a satellite cell, and it can’t fix a damaged muscle fiber. “It’s a one-way street,” Rudnicki says. Not all the satellite cells taken from donors and grown in a lab dish have reached that point of no return, but most of them have, he says. And as time goes by in the lab, more and more of them reach it.

Pre-myoblast satellite cells would be needed for repair of damaged tissue.

Rudnicki believes that cell stage isn’t the only important factor in cell transplantation. The environment into which the cells are placed may be as important.

Dealing with the immune system’s response to the new cells and, in Duchenne MD, the dystrophin that the system may regard as “foreign” if the body hasn’t encountered it before, is crucial, he notes.

He hypothesizes that younger donor cell recipients may have more receptive muscles and a more tolerant immune system, although he isn’t certain. But Rudnicki is certain that scarring in the muscle must be minimized for cell transplantation to work.

“I think that’s one area that we need to pay more attention to,” he says. “We need to learn more about the mechanisms that cause scarring and learn how to stop that.”

And, Rudnicki notes, there’s also more than one reason to understand how cells choose a muscle career path.

“In my view,” he says, “cell transplant therapy is still a very technically challenging approach. If we could identify a drug that would, even in a modest way, stimulate the activity, expansion or self-renewal of [the patient’s own] muscle satellite cells, we could perhaps make Duchenne muscular dystrophy into a chronic disease rather than a lethal disease. I think that’s an approach we shouldn’t forget about.”

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