Chemical cocktail creates new ways to generate muscle stem cells

A research team led by UCLA has identified a chemical cocktail that enables the production of large amounts of muscle stem cells, which can renew themselves and give rise to all types of skeletal muscle cells.

The advancement can lead to the development of stem cell therapies for muscle loss or damage due to injury, age or illness. The research was published in Natural Biomedical Engineering.

Muscle stem cells are responsible for muscle growth, recovery and rebirth after injury throughout a person’s lifetime. In adults, muscle stem cells are calm – they remain inactive until called upon to respond to injuries by making self-replication and creating all the cell types needed to repair damaged tissue.

But that regenerative ability decreases as people get older; it can also be affected by traumatic injuries and genetic diseases such as Duchenne muscular dystrophy.

“Muscle stem cell-based therapies show great promise in improving muscle regeneration, but current methods of generating patient-specific muscle stem cells can take months,” said Song Li, senior author of the study and member of the Eli and Edythe Broad Center for Regenerative Medicine and stem cell research at UCLA.

Li and his colleagues have identified a chemical cocktail – a combination of the root extract forskolin and the small molecule RepSox – that can efficiently create a large amount of muscle stem cells within ten days. In mouse studies, the researchers showed two potential ways in which the cocktail could be used as a therapy.

The first method uses cells that occur in the skin, called dermal myogenic cells, which have the ability to become muscle cells. The team discovered that treating dermal myogenic cells with the chemical cocktail drove them to produce large amounts of muscle stem cells, which could then be transplanted into injured tissue.

Li’s team tested the approach in three groups of mice with muscle injuries: adult (8-week-old) mice, elderly (18-month-old) mice, and adult mice with a genetic mutation similar to that caused by Duchenne in humans.

Four weeks after the cells were transplanted, the muscle stem cells integrated into the damaged muscle and significantly improved the muscle function in all three groups of mice.

For the second method, Li’s team used nanoparticles to deliver the chemical cocktail into damaged muscle tissue. The nanoparticles, which are about one-hundredth the size of a grain of sand, are made of the same material as soluble surgical stitches, and are designed to slowly release the chemicals as they break down.

The second approach also elicited a robust recovery response in all three species of mice. When the nanoparticles are injected into the injured muscle, they migrate through the injured area and release chemicals, which activate the resting muscle cell cells to begin dividing.

Although both techniques were successful, the main advantage of the second one is that it eliminated the need for growing cells in the laboratory – all the muscle stem cell activation and regeneration takes place in the body.

The team was particularly surprised to discover that the second method was effective even in elderly mice, despite the fact that as animals age, the environment surrounding and supporting muscle stem cells becomes less effective.

“Our chemical cocktail has enabled muscle stem cells in older mice to overcome their adverse environment and launch a robust recovery response,” said Li, who is also chair of bio-engineering at the UCLA Samueli School of Engineering and professor of medicine. the David Geffen School of Medicine at UCLA.

In future studies, the research team will try to replicate the results in human cells and monitor the effects of the treatment in animals for a longer period of time. The experiments should help determine if any of the approaches can be used as a one-time treatment for patients with severe injuries.

Li noted that neither approach can solve the genetic defect caused by Duchenne or other genetic muscular dystrophies. However, the team envisages that muscle stem cells generated by a healthy donor’s skin cells can be transplanted into a muscular dystrophy patient’s muscles – as in the lungs – which can extend their lifespan and improve their quality of life.