An unexpected link: immune cells send muscle injury signal to activate stem cell regeneration

We’ve written many blogs over the years about research focused on muscle stem cell function . Those stories describe how satellite cells, another name for muscle stem cells, lay dormant but jump into action to grow new muscle cells in response to injury and damage. And when satellite function breaks down with aging as well as with diseases like muscular dystrophy, the satellite cells drop in number and/or lose their capacity to divide, leading to muscle degeneration.

Illustration of satellite cells within muscle fibers. Image source: APSU Biology

One thing those research studies don’t focus on is the cellular and molecular signals that cause the satellite cells to say, “Hey! We need to start dividing and regenerating!” A Stanford research team examining this aspect of satellite cell function reports this week in Nature Communications that immune cells play an unexpected role in satellite cell activation. This study, funded in part by CIRM, provides a fundamental understanding of muscle regeneration and repair that could aid the development of novel treatments for muscle disorders.

ADAMTS1: a muscle injury signal?
To reach this conclusion, the research team drew upon previous studies that indicated a gene called Adamts1 was turned on more strongly in the activated satellite cells compared to the dormant satellite cells. The ADAMTS1 protein is a secreted protein so the researchers figured it’s possible it could act as a muscle injury signal that activates satellites cells. When ADAMTS1 was applied to mouse muscle fibers in a petri dish, satellite cells were indeed activated.

Next, the team examined ADAMTS1 in a mouse model of muscle injury and found the protein clearly increased within one day after muscle injury. This timing corresponds to when satellite cells drop out of there dormant state after muscle injury and begin dividing and specializing into new muscle cells. But follow up tests showed the satellite cells were not the source of ADAMTS1. Instead, a white blood cell called a macrophage appeared to be responsible for producing the protein at the site of injury. Macrophages, which literally means “big eaters”, patrol our organs and will travel to sites of injury and infection to keep them clean and healthy by gobbling up dead cells, bacteria and viruses. They also secrete various proteins to alert the rest of the immune system to join the fight against infection.

Immune cell’s double duty after muscle injury: cleaning up the mess and signaling muscle regeneration
To confirm the macrophages’ additional role as the transmitter of this ADAMTS1 muscle injury signal, the researchers generated transgenic mice whose macrophages produce abnormally high levels of ADAMTS1. The activation of satellite cells in these mice was much higher than in normal mice lacking this boost of ADAMTS1 production. And four months after birth, the increased activation led to larger muscles in the transgenic mice. In terms of muscle regeneration, one-month old transgenic mice recovered from muscle injury faster than normal mice. Stanford professor Brian Feldman, MD, PhD, the senior author of the study, described his team’s initial reaction to their findings in an interview with Scope, Stanford Medicine’s blog:

“While, in retrospect, it might make intuitive sense that the same cells that are sent into a site of injury to clean up the mess also carry the tools and signals needed to rebuild what was destroyed, it was not at all obvious how, or if, these two processes were biologically coupled. Our data show a direct link in which the clean-up crew releases a signal to launch the rebuild. This was a surprise.”

Further experiments showed that ADAMTS1 works by chopping up a protein called NOTCH that lies on the surface of satellite cells. NOTCH provides signals to the satellite cell to stay in a dormant state. So, when ADAMTS1 degrades NOTCH, the dormancy state of the satellite cells is lifted and they begin to divide and transform into muscle cells.

A pathway to novel muscle disorder therapies?
One gotcha with the ADAMTS1 injury signal is that too much activation can lead to a depletion of satellite cells. In fact, after 8 months, muscle regeneration actually weakened in the transgenic mice that were designed to persistently produce the protein. Still, this novel role of macrophages in stimulating muscle regeneration via the secreted ADAMTS1 protein opens a door for the Stanford team to explore new therapeutic approaches to treating muscle disorders:

“We are excited to learn that a single purified protein, that functions outside the cell, is sufficient to signal to muscle stem cells and stimulate them to differentiate into muscle,” says Dr. Feldman. “The simplicity of that type of signal in general and the extracellular nature of the mechanism in particular, make the pathway highly tractable to manipulation to support efforts to develop therapies that improve health.”

Using satellites to build bigger biceps

Arnold Schwarzenegger: Photo courtesy Awesome-Body.info

Arnold Schwarzenegger:
Photo courtesy Awesome-Body.info

There are several ways you can build bigger, stronger muscles. You can take the approach favored by our former Governor, Arnold Schwarzenegger, and pump iron till your biceps are as inflated as a birthday balloon. Or you could follow the lead of a research team we are funding and try to use stem cells to do the trick.

Our muscles contain a group of stem cells called satellite cells. These normally lie dormant until the muscle is damaged and then they spring into action to repair the injury. However, satellite cells are relatively rare and are hidden in the muscle itself, making them hard to find and notoriously difficult to study. In the past researchers have struggled to get these satellite cells to grow outside the body, which made it difficult to study muscle regeneration and develop new ways of treating muscle problems.

Finding a solution

Now a team at the University of California, San Francisco has found a solution to the problem. They started by analyzing samples of 7 different kinds of muscles (in the body, legs and head) from 43 patients. In all but two samples they found that the gene PAX7 was specifically turned on in satellite cells and the PAX7 protein was present with little variation from one muscle group to another.

Upon further sleuthing, they discovered that PAX7-positive satellite cells were the real deal because they also expressed two common cell surface markers of human satellite cells: CD29 and CD56.

The researchers then transplanted PAX7-positive cells into mice that had experienced muscle injuries. As they report in the journal Stem Cell Reports these cells not only engrafted in the mice but they also created hundreds of human-derived muscle fibers. This finding shows that satellite cells were regenerating and potentially helping to heal the damaged muscle.

What’s next

As always, anything done in mice is interesting but still needs to be replicated in people before we know for sure we are on to something.

In their conclusion the team freely admit this is just a first step but, compared to where we were before, it’s a very important step. As senior author Jason Pomerantz says:

“This is the first definitive experimental description of adult human endogenous muscle stem cell function.”

Harnessing the power of satellite cells would be of tremendous benefit to people suffering from facial paralysis, loss of hand function or muscle-wasting diseases such as sarcopenia, and could even be used as a way to deliver gene therapy to people with muscular dystrophies.

Using satellite cells to do all that, would be out of this world.