Regenerative therapies for muscular disease

A new report in the June 1 issue of the journal Cell, a publication of Cell Press, confirms the existence of some apparently uncommitted stem cells amongst cells responsible for generating the bulging biceps of body builders and the rippling abs of fitness buffs.

The findings could lead to new muscle-regenerating therapies-including cell transplantation regimens and stem cell-replenishing drugs-for people with various muscle-wasting diseases, including muscular dystrophies. Ultimately, such treatments might also help keep people strong as they age, according to the researchers.

A team led by Michael Rudnicki of the Ottawa Health Research Institute in Canada found that so-called satellite cells in muscle actually include a mix of cells already committed to their muscular fate and others that behave like more versatile stem cells. The cells had widely been considered by scientists as a homogeneous population of dedicated muscle progenitors. Moreover, Rudnicki's team showed that injection of the "satellite stem cells" into the muscles of mice successfully replenished the animals' regenerative reservoir of cells.

"We've found that there are two types of satellite cell-90% that are already committed to becoming muscle and another 10% with characteristics normally attributed to stem cells," Rudnicki said. "It's not been shown yet, but these muscle stem cells might even have the capacity to make other tissues, such as bone and fat."

"We've also shown that these satellite stem cells, when transplanted into muscle, can repopulate the regenerative cell niche. This is a very significant advance in our understanding of satellite cell biology that will require us to rethink decades of research. It also opens new avenues for therapeutic treatment of muscular diseases."

Skeletal muscle fibers are essentially long, tubular cells, each of which includes hundreds of nuclei. The fibers are surrounded by a coating of collagen and other glycoproteins with satellite cells sandwiched in between. First discovered in the 1960s, satellite cells are known to be responsible for the growth, maintenance, and repair of skeletal muscle after birth. The normally quiet restorative cells spring into action in response to the stress of weight-bearing or trauma.

Yet much about the mechanisms controlling satellite cells' identity and development had remained uncertain, Rudnicki said. Earlier studies had even suggested that satellite cells might originate from muscle cells that had essentially regressed, or dedifferentiated, to a more primitive developmental state.

In the new study, the researchers took a closer look at the molecular profiles of satellite cells isolated from mouse muscle. They showed that the satellite cells consist of two classes defined by the activity or inactivity of a gene called Myf-5.

Moreover, that genetic difference gave rise to an important distinction in the satellite cells' behavior. Cells without active Myf-5 divide asymmetrically-a characteristic commonly seen among stem cells. That lopsided cell division produced one "daughter" like its parent, exhibiting a stem cell-like capacity for self renewal, and another Myf-5 positive cell.

The researchers also showed that satellite cells in which Myf-5 was switched on, when injected into the muscles of mice, continued down the road toward becoming muscle. In contrast, transplantation of Myf-5 negative cells "extensively contributed to the satellite cell reservoir throughout the injected muscle."

The findings led the researchers to conclude that satellite stem cells could be used for direct transplantation into diseased muscle, noting that molecular characterization of satellite stem cells should lead to identification of markers enabling their prospective isolation from human muscle tissue.

"Alternatively," they added, "understanding the molecular regulation of satellite stem cell symmetric versus asymmetric cell division will lead to identification of biologics or small drugs that specifically target the relevant pathway leading to satellite stem cell expansion."-Cell Press

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