stem cells called satellite cells

Signaling to muscle satellite cells

Studies reveal new mechanisms essential to muscle growth and repair

Three papers this month indicate how muscle regeneration could be induced via cell therapy or delineate the mechanisms by which it happens naturally.

Researchers led by Rita Perlingeiro at the University of Texas Southwestern Medical School, differentiated mouse embryonic stem cells into muscle progenitor cells which restored function when infused into mice with a mouse version of Duchenne's muscular dystrophy, a wasting disease1. The researchers genetically engineered embryonic stem cells to produce a protein (the transcription factor Pax3) that promotes muscle development in embryos. Initially, transplanting these cells produced teratomas so the researchers selected a subset of this population based on cell markers and tried again. When transplanted into mouse muscle or infused into the bloodstream, these cells did not form tumours but instead engrafted widely in diseased muscle tissue and improved its function, at least by some measures. Though these results are too early to be tried to humans, they support the eventual use of cell-based therapies for certain muscle-wasting diseases.

Normally, adult skeletal muscle is regenerated by stem cells called satellite cells. When activated by muscle damage, the cells proliferate and differentiate into myoblasts. These then fuse with mature myofibres to generate new tissue. The molecular signals governing these events are still obscure, but in a recent issue of Cell Stem Cell, researchers at Stanford University describe a time-sensitive regulatory pathway that determines the fate of satellite cells and, ultimately, the success of muscle repair2.

Thomas Rando and his team showed that levels of secreted signalling proteins called Wnts gradually increase in the muscle fibres and satellite cells of adult mice after injury, and drive the conversion of proliferating satellite cells into differentiated myoblasts. Wnts are well-known signalling molecules that are active in muscle tissue during development and are involved in the build-up of connective tissue in the muscles of ageing mice3. The new experiments showed the Stanford researchers that timing is everything. Inhibition of Wnt signalling immediately after injury had no effect on muscle repair, whereas later inhibition led to fewer new muscle fibres and impaired regeneration. The authors interpreted this to mean that Wnts are involved with the switch between proliferation and differentiation.

The timing of this switch was so critical to the formation of healthy new muscle that the researchers wanted to determine how it is controlled. They had previously discovered that another signalling pathway, initiated by the receptor Notch, was essential for cell proliferation early in muscle regeneration in mice4, and set out to determine if there was a relationship between the functions of Notch and Wnt signalling. They did indeed show direct molecular cross-talk between the two signalling pathways in satellite cells via the intracellular signaling molecule GSK3, which is downstream of both. When Notch is active Wnt signalling is suppressed, and vice versa.

http://www.nature.com/stemcells/2008/0801/080131/full/stemcells.2008.29.html