by Krista Conger

Resting, adult stem cells of many types of tissues enter a reversible "alert" phase in response to a distant injury, according to a study in mice by researchers at the Stanford University School of Medicine.

The study describes for the first time a new phase in the resting portion of the cell cycle. It also explains how stem cells prime themselves to rapidly respond to tissue damage without prematurely committing to energetically expensive (and possibly unnecessary) cell division. These alert cells are distinct from fully resting or fully activated stem cells, and they divide and repair subsequent tissue damage much more quickly than do fully resting stem cells.

The findings imply that nearly any type of injury may put stem cells throughout the body on notice for possible future regenerative needs.

"These alert stem cells changed markedly in response to a distant muscle injury," said Thomas Rando, MD, PhD, professor of neurobiology and neurological sciences. "They are partially awake and are poised to respond to additional challenges and make new tissue as needed. This is a systemic, or whole-body, response to injury that has never been seen before."

The researchers suggest the alert phase represents a novel form of cellular memory similar to that displayed by the immune system, which relies upon prior experiences to drive future responses.

Rando, who also directs Stanford's Glenn Laboratories for the Biology of Aging, is the senior author of the study, published online May 25 in Nature. Postdoctoral scholar Joseph Rodgers, PhD, is the lead author.

Resting state?

The researchers were studying the response of mouse muscle stem cells, or satellite cells, to muscle injury. Conventional wisdom holds that adult stem cells are by nature quiescenta term that indicates a profound resting state characterized by small size and no cell division. It's a kind of cellular deep freeze. In contrast, most other cells cycle through rounds of DNA replication and cell division in discrete, well-defined phases. A quiescent stem cell can "wake up" and enter the cell cycle in response to local signals of damage or other regeneration needs.

Rando and his colleagues were studying this activation process in laboratory mice by watching how muscle stem cells in one leg respond to a nearby muscle injury in the same leg. (Mice were anesthetized prior to a local injection of muscle-damaging toxin; they were given pain relief and antibiotics during the recovery period.) The researchers had planned to observe the quiescent muscle stem cells in the uninjured leg as a control for their experiment. However, they instead saw something unexpected.

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