Unexpected role of macrophages in the activation of muscle stem cells

Scientists from Stanford University, USA, have found that the immune cells play an important role in restoring muscle tissue by directly affecting stem cells. The results of the study were published on September 22, 2017 in Nature Communications.

Previous studies have shown that muscle stem cells or, as they are also called, satellite cells, are usually lay dormant, being activated to repair injuries resulting from trauma. Over time, in the process of aging the satellite cells are destroyed and lose the ability to divide, leading to muscle degeneration. A similar picture is observed in such diseases as muscular dystrophy.

Stanford research team decided to study molecular signals that activate muscle stem cells and cause them to divide. So far, such studies have not been conducted. A fundamental understanding of muscle regeneration and repair could aid the development of new methods for treating many diseases associated with disorders in muscle tissue.

The research group was interested in the results of previous studies in which it was shown that the activity of the Adamts1 gene increased in activated muscle stem cells. This gene secretes the protein with the same name, ADAMTS1 (A Disintegrin And Metalloproteinase With Thrombospondin 1), so the researchers suggested that it’s possible it could act as a muscle injury signal that activates satellites cells. The impact of ADAMTS1 on mouse muscle fibers in the petri dish really activated the stem cells.

Then a team of scientists investigated ADAMTS1 for muscle damage on a model of mice. They found that the protein clearly increased within one day after a muscle injury. This timing corresponds to the activation time of the satellite cells, during which they begin to divide and differentiate into new muscle cells. However, further studies showed that stem cells were not the source of ADAMTS1. Responsible for protein production in places of injury were white blood cells, called macrophages.

Macrophages (literally means “big eaters”, from the Greek, μακρός – large, and φάγος – to eat) guard our organs and will migrate to damaged or infected areas, cleaning them by absorbing dead cells, bacteria and viruses. They also secrete various proteins to alert the immune system to join the fight against infection.

To confirm the role of macrophages as a transmitter of the ADAMTS1 muscle injury signal, the researchers generated transgenic mice whose macrophages produced abnormally high levels of ADAMTS1.

The activation of satellite stem cells in these mice was significantly higher than in normal mice lacking this boost of ADAMTS1 production. Four-month transgenic mice possessed a much larger muscle mass. One-month old transgenic animals recovered much more quickly from the muscular trauma compared to conventional mice.

Stanford professor Brian Feldman, MD, lead author of the study, described his team’s initial reaction to their results in an interview:

“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 studies have shown that ADAMTS1 works by chopping up a protein called NOTCH that lies on the surface of satellite cells. NOTCH produces signals that help the satellite cells to stay in a dormant state. Thus, when ADAMTS1 destroys NOTCH, stem cells are activated, they begin to divide and differentiate into muscle stem cells.

One gotcha in the work of ADAMTS1 is that it’s too high activity can lead to depletion of satellite cells. In fact, after 8 months, muscular regeneration significantly weakened in the transgenic mice, although they were derived with the expectation of a constant protein production.

Nevertheless, this new role of macrophages in stimulating muscle regeneration via the secreted ADAMTS1 protein opens new opportunities for the Stanford team to explore new therapeutic approaches to the treatment of muscle diseases.

“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.”