Researchers at the Salk Institute have uncovered a mechanism by which stem cells can help regenerate muscles. The discovery could provide a new drug target for repairing muscles after injury or rebuilding muscle mass lost during the normal aging process.

The breakthrough started with a set of proteins called Yamanaka factors, which have long been studied as a key part of stem cell therapy. These factors are used to convert regular cells – most commonly skin cells – into what are known as induced pluripotent stem cells (iPS), which can then go on to differentiate into a variety of other cell types. That in turn helps regenerate tissue. But exactly how the Yamanaka factors worked their magic remained a mystery.

“Our laboratory previously showed that these factors can rejuvenate cells and promote tissue regeneration in live animals,” says Chao Wang, first author of the study. “But how this happens was not previously known.”

So the Salk team set out to investigate that mechanism. In muscle regeneration, Yamanaka factors seem to act on muscle stem cells called satellite cells. These don’t reside in the muscle fibers themselves but in a “niche” between that and a layer of connective tissue called the basal lamina.

In tests in mice, the researchers introduced Yamanaka factors into one of two areas – the muscle fibers or the niche containing the satellite cells. Counter-intuitively, the team found that trying to directly stimulate the muscle stem cells didn’t activate them. But when the factors were added to the muscle fibers, the message seemed to cross over into the niche and activate the satellite cells to boost muscle regeneration.

Scientists discover how stem cells trigger muscle regeneration
A comparison between a control group (top) and the experimental group (bottom), which received Yamanaka factors in the muscle fiber. The pink blobs represent a muscle stem cell marker called Pax7

Salk Institute

On closer inspection, the researchers found that the Yamanaka factors reduced levels of a protein called Wnt4 in the niche, which seems to be what activates the satellite cells. That protein could be a useful target for future drugs that may help boost muscle regeneration.

“Our laboratory has recently developed novel gene-editing technologies that could be used to accelerate muscle recovery after injury and improve muscle function,” says Izpisua Belmonte, corresponding author of the study. “We could potentially use this technology to either directly reduce Wnt4 levels in skeletal muscle or to block the communication between Wnt4 and muscle stem cells.”

With this new target in the crosshairs for future studies, scientists can begin to investigate new drugs that help regenerate muscles after injuries, or to slow muscle loss during the aging process or disease.

The research was published in the journal Nature Communications.

Source: Salk Institute

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