VA Palo Alto Health Care System
VA/Stanford Scientists Work To Understand The Aging Process
A tiny piece of RNA plays a key role in determining when muscle stem cells from mice activate and start to divide, according to researchers at the VA Palo Alto Health Care System (VAPAHCS) and Stanford University School of Medicine. The finding may help scientists learn how to prepare human muscle stem cells for use in therapies for conditions such as muscular dystrophy and aging by controlling their activation state.
"We'd like to understand the aging process at a very fundamental level," said Thomas Rando, MD, PhD, VAPAHCS researcher and Stanford professor of neurology and neurological sciences. "That will allow us to move toward more therapeutic applications. Can we use what we've learned to convert old stem cells, which seem to have lost their responsiveness to activation cues, into young stem cells? We may one day be able to develop approaches that enhance tissue repair by enhancing stem cell function."
It's the first time that a small regulatory RNA, called a microRNA, has been implicated in the maintenance of the adult stem cell resting, or quiescent, state.
"Although on the surface the quiescent state seems to be relatively static, it's quite actively maintained. We've found that changing the levels of just one specific microRNA in resting muscle stem cells, however, causes them to spring into action."
Unlike stem cells in the blood or skin, muscle stem cells spend most of their lives nestled in the surrounding tissue. "They don't do much most of the time," said Rando. "They remain in a quiescent state for most of a person's life. When you injure your muscle, however, they begin dividing to repair the damage." Like all adult stem cells, each muscle stem cell becomes two daughter cells: one with stem cell properties, and the other that continues dividing to become mature muscle cells and fibers to replenish those that are damaged. Without such "asymmetric" division, the stem cells would quickly be depleted after injury.
Pinpointing exactly what calls the stem cells to begin dividing is an important first step to using them in human therapies. It's also a key to understanding how muscles age and why they become less able over time to repair normal wear and tear.
"If you're going to use muscle stem cells as a therapy for disease or aging, you want to be able to transplant cells that have the greatest potential to make new muscle in the recipient," said Rando. "The quiescent state most closely resembles how they are in the body. If you allow them to divide in the lab before transplantation, they are not as effective. This microRNA may allow us to toggle the cells back and forth between the actively dividing and quiescent states."
In the future, the researchers will continue to look at the unique features of quiescent muscle stem cells, including those involved in normal aging, but this early research in the area has set the foundation for future investigators.