Healing Injured Muscles: How Stem Cells from Subcutaneous Fat Help Regenerate Muscle Tissue
Skeletal muscle is a hard-working tissue that enables us to move around and interact with our surroundings. Although capable of withstanding significant force, it is among the most commonly injured tissues in the human body. Minor injuries to muscle — such as the microscopic tears inflicted by weightlifting — heal rapidly and usually cause a net strengthening of the tissue. However, major injuries to muscles can cause serious complications and may take years to heal.
The mechanism by which muscle regrows following an injury is only partially understood. Past research has shown that a group of stem cells called fibroadipogenic progenitors (FAPs) play a significant role in the healing process. These cells, which normally reside within the skeletal muscle, divide to generate specialized stem cells following a muscle injury. These stem cells then divide and produce many new myocytes (muscle cells).
Recently, a group of researchers noticed that the immediate increase in stem cells at an injury site was too vast to be attributed to the replication of FAPs alone. They hypothesized that some of the stem cells migrated to skeletal muscle from different tissues. These researchers had previously studied adipose stromal cells (ASCs), a type of stem cell that originates in subcutaneous adipose tissue (the layer of fat directly beneath the skin). Their knowledge of the similarities between ASCs and FAPs led the researchers to investigate the role of ASCs in responding to muscle injuries.
The researchers set up an experiment in which they artificially injured the muscles of live mice by injecting their quadriceps muscle with a combination of glycerol and myotoxin. One day later, they evaluated the concentration of stem cells in the quadriceps muscles and the adjacent subcutaneous fat. They found that there had been a sharp increase in stem cells in the muscle and a sharp decline in the ASC content of subcutaneous fat. This supported their hypothesis that ASCs could migrate out of their home tissue.
The researchers next evaluated the response of ASCs in vitro (outside of a live organism) to serum (the liquid component of blood). They immersed cultures of ASCs in serum that had been taken from mice and humans with minor exercise-induced muscle damage. Under a microscope, they observed that the ASCs were strongly stimulated to migrate when exposed to serum from both mice and humans. This suggested that the injured muscles had released a chemical into the serum that prompted ASCs to respond to the site.
The researchers also performed an in vivo experiment (on live animals) to test whether ASCs actually migrate from the subcutaneous fat to the muscle. They attached a green fluorescent protein (GFP) marker to the surface of each ASC in a sample of subcutaneous fat, then grafted the sample into the subcutaneous fat of a live mouse. One week later, they induced muscle injuries in the mice by humanely injecting their quadriceps muscles with either cardiotoxin or glycerol. Later, they extracted and examined the muscle tissue and found that cells bearing the GFP marker had migrated into the muscle. This experiment demonstrated that ASCs do migrate from subcutaneous fat to skeletal muscle after an injury.
Figure 1. This experiment conclusively demonstrated that stem cells from subcutaneous adipose tissue (ASCs) infiltrate muscle tissue after an injury.
To evaluate the necessity of ASCs during the healing process, the researchers conducted an experiment in which they inhibited ASC infiltration of damaged muscles. They removed the subcutaneous fat of a group of mice (thus eliminating their ASC population entirely) and inflicted muscle injuries. They administered injections of ASCs to a subset of this group. The mice that received the ASC injections healed at a much faster rate than the mice that did not. This demonstrated that ASCs contribute significantly to the healing process.
The results of this study show that stem cells from subcutaneous fat tissue play an important role in healing skeletal muscle injuries. Damage to muscle releases chemical factors into the blood that recruit ASCs from subcutaneous fat tissue to respond to the site. Together with the FAPs already present in the muscle, the ASCs promote healing by producing a population of stem cells that regenerate the tissue. This repairs and strengthens the muscle.
