The chemical cocktail creates new pathways for the generation of muscle stem cells

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

Advancement may lead to the development of stem cell-based therapies for muscle loss or damage due to injury, age or illness. The research was published in Nature Biomedical Engineering.

Muscle stem cells are responsible for muscle growth, repair and regeneration after injury throughout a person’s life. In fully grown adults, muscle stem cells are quiescent – they remain inactive until they are called upon to respond to the injury through self-replication and the creation of all types of cells necessary to repair damaged tissue.

But this regenerative capacity decreases as people get older; it can also be compromised by traumatic injuries and genetic diseases, such as Duchenne muscular dystrophy.

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

Li and his colleagues identified a chemical cocktail – a combination of forskolin root extract and the small molecule RepSox – that can efficiently create large numbers of muscle stem cells in 10 days. In studies with rats, the researchers demonstrated two potential ways in which the cocktail could be used as therapy.

The first method uses cells found in the skin called dermal myogenic cells, which have the ability to become muscle cells. The team found that treatment of dermal myogenic cells with the chemical cocktail led them to produce a large number of muscle stem cells, which could be transplanted into the injured tissue.

Li’s team tested this approach in three groups of mice with muscle injuries: adult mice (8 weeks), elderly mice (18 months) and adult mice with a genetic mutation similar to the one that causes Duchenne in humans.

Four weeks after the cell transplant, the muscle stem cells integrated with the damaged muscle and significantly improved muscle function in all three groups of mice.

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

The second approach also produced a robust repair response in all three types of mice. When injected into the injured muscle, the nanoparticles migrated throughout the injured area and released chemicals, which activated the stem cells of the quiescent muscle to start dividing.

While both techniques have been successful, the main benefit of the second is that it eliminated the need for cell growth in the laboratory – all muscle stem cell activation and regeneration takes place within the body.

The team was particularly surprised to find that the second method was effective even in elderly rats, despite the fact that, as animals age, the environment that surrounds and supports muscle stem cells becomes less effective.

“Our chemical cocktail allowed muscle stem cells in elderly rats to overcome their adverse environment and launch a robust repair response,” said Li, who is also the head of bioengineering at the UCLA Samueli School of Engineering and professor of medicine at the School of David Geffen. Medicine at UCLA.

In future studies, the research team will try to replicate the results in human cells and monitor the effects of therapy on animals for a longer period. The experiments should help determine whether either approach can be used as a single treatment for patients with serious injuries.

Li noted that none of the approaches would fix the genetic defect that causes Duchenne or other genetic muscular dystrophies. However, the team predicts that muscle stem cells generated from skin cells from a healthy donor can be transplanted into the muscle of a patient with muscular dystrophy – such as in the lungs – which can extend their life expectancy and improve your quality of life.