The researchers termed the response an “alert” state; the cells are no longer resting deeply, but are also not yet committed to possibly unnecessary action.
The team was studying the response of mouse muscle stem cells, or satellite cells, to muscle injury. Conventional wisdom holds that adult stem cells are by nature quiescent — a 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.
“The muscle stem cells in the uninjured leg had definitely changed. They were very clearly biochemically different from completely dormant, quiescent cells, and from fully activated stem cells. We termed this state an ‘alert’ state of quiescence.” said Rando, who is director of the Rehabilitation Research & Development Center of Excellence at the Veterans Affairs Palo Alto Health Care System.
These alert stem cells were able to respond to subsequent, nearby damage much more quickly and efficiently than completely quiescent cells, the researchers found. They also learned that the stem cells’ response encompasses several tissue types in addition to the one in which the injury occurred. More from the release:
Surprisingly, the muscle stem cells also became alert in response to bone or minor skin injuries — injuries in which the cells are not known to play any regenerative role.
Conversely, other non-muscle adult stem cells, including hematopoietic stem cells in the bone marrow and mesenchymal stem cells in the muscle, became alert in response to muscle damage.
“It is clear that this alert state is a systemic response.” said Rando.
The findings help explain some long-standing questions about the cell cycle, in which cycling cells co-exist with other, quiescent cells. As Rando, who also directs Stanford’s Glenn Laboratories for the Biology of Aging, explained:
Researchers studying cellular quiescence in the laboratory decades ago noticed that, when you withdraw growth factors, cells stop dividing. They observed that there were different ways a cell could exist in that state. But until now, no one has described this phenomenon in detail or investigated its physiological consequences. They were seeing what we have now explained on a molecular level and in stem cells in the body — the first real evidence of a second state of quiescence that allows much more rapid and effective tissue repair.
- Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK, Brunson C, Mastey N, Liu L, Tsai CR, Goodell MA, & Rando TA (2014). mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert. Nature PMID: 24870234