23 November 2022

Against cancer and sarcopenia

Muscle stem cells, which generate new muscle cells after injury or physical exertion, lose their effectiveness with age. Researchers from Stanford Medical University have shown that old mice restore muscle strength to the level of young animals after receiving treatment with antibodies that block the pathway mediated by CD47 glycoprotein.

CD47, or the "don't eat me" molecule, is better known as a target for cancer immunotherapy than for muscle regeneration. It is detected in large quantities on the surface of cancer cells, protecting them from immune cells that patrol the body in search of dysfunctional or atypical cells. It turned out that old muscle stem cells can use a similar approach to avoid being destroyed by the immune system.

Innovative technique

It is known that muscle stem cells lose their ability to divide rapidly with age in response to injury or physical exertion. The cause of this phenomenon has been poorly studied, since it is extremely difficult to isolate different subpopulations of these cells for study. Ermelinda Porpiglia and co-authors used the method of single-cell mass cytometry to identify subpopulations of mouse muscle stem cells whose surface markers change in proportion to the age of the animals.

Membrane glycoprotein CD47 was found in high concentrations on the surface of some muscle stem cells and in lower concentrations on the surface of others. In older animals, CD47-rich cells predominate.

This discovery was unexpected because CD47 is primarily known as an immunoregulator. But, like cancer cells, old stem cells can use the CD47 "don't eat me" signal to avoid an attack by the immune system.

The researchers found that high levels of CD47 on the surface of muscle stem cells correlate with a decrease in their function. These cells were less able to consolidate and form new muscles when transplanted into the leg muscles of other mice compared to cells with lower CD47 levels.

Further studies have shown that the protein thrombospondin, which binds to CD47 on the surface of muscle stem cells, suppresses the activity of muscle stem cells. Thrombospondin accumulates in skeletal and cardiac muscle cells with age, but its expression in skeletal muscles decreases after exercise.

Antibodies that recognize thrombospondin and block its ability to bind to CD47 dramatically change the activity of muscle stem cells: cells isolated from old animals divided more steadily when grown in the presence of antibodies, and when antibodies were injected into the leg muscles of old mice, the animals developed larger and stronger muscles than in control animals. The antibodies helped older animals recover from injury in a similar way to younger mice and faster than older animals receiving placebo.

Antibodies to thrombospondin had no effect on mice with a knockout gene encoding CD47, which indicates the crucial importance of CD47 interaction with thrombospondin for the activity of muscle stem cells in response to aging or traumatic injury.


Potential for muscle recovery

Treatment with antithrombospondin antibodies is a local and temporary way to activate muscle stem cells in experimental animals. Perhaps someday the introduction of antibodies to thrombospondin in certain areas of the body will restore muscle tissue in the elderly or patients with muscle weakness caused by disease or surgery.

The study points to the important role of CD47 in several biological processes. It is planned to find out whether antibodies blocking the "don't eat me" signal from CD47 will stimulate the immune system to remove old, non-functional muscle stem cells.

It remains unclear whether cancer immunotherapy targeting CD47 also blocks the thrombospondin pathway. If this is the case, then it is quite possible that antibodies against CD47 can prevent cachexia – the depletion of muscle tissue that usually develops in cancer patients.

Article by E.Porpiglia et al. Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration published in the journal Cell Stem Cell.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Stanford Medicine: Old mice regain leg strength after antibody treatment, Stanford Medicine researchers find.

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