Myosatellite cells

Myosatellite cells or satellite cells are small mononuclear progenitor cells with virtually no cytoplasm found in mature muscle. They are found sandwiched between the basement membrane and sarcolemma (cell membrane) of individual muscle fibers, and can be difficult to distinguish from the sub-sarcolemmal nuclei of the fibers. Satellite cells are able to differentiate and fuse to augment existing muscle fibers and to form new fibers. These cells represent the oldest known adult stem cell niche, and are involved in the normal growth of muscle, as well as regeneration following injury or disease.

In undamaged muscle, the majority of satellite cells are quiescent; they neither differentiate nor undergo cell division. In response to mechanical strain, satellite cells become activated. Activated satellite cells initially proliferate as skeletal myoblasts before undergoing myogenic differentiation.

Genetic markers of satellite cells
Satellite cells express a number of distinctive genetic markers. Current thinking is that all satellite cells express PAX7 and PAX3

Activated satellite cells express myogenic transcription factors, such as Myf5 and MyoD. They also begin expressing muscle-specific filament proteins such as desmin as they differentiate.

The field of satellite cell biology suffers from the same technical difficulties as other stem cell fields. Studies rely almost exclusively on Flow cytometry and Fluorescence Activated Cell Sorting (FACS) analysis, which gives no information about cell lineage or behaviour. As such, the satellite cell niche is relatively ill-defined and it is likely that it consists of multiple sub-populations.

Function in muscle repair
When muscle cells undergo injury, quiescent satellite cells are released from beneath the basement membrane. They become activated and re-enter the cell cycle. These dividing cells are known as the "transit amplifying pool" before undergoing myogenic differentiation to form new (post-mitotic) myotubes. There is also evidence suggesting that these cells are capable of fusing with existing myofibers to facilitate growth and repair.

The process of muscle regeneration involves considerable remodeling of extracellular matrix and, where extensive damage occurs, is incomplete. Fibroblasts within the muscle deposit scar tissue, which can impair muscle function, and is a significant part of the pathology of muscular dystrophies.

Satellite cells proliferate following muscle trauma (Seale, et al., 2003) and form new myofibers through a process similar to foetal muscle development (Parker, et al., 2003). After several cell divisions, the satellite cells begin to fuse with the damaged myotubes and undergo further differentiations and maturation, with peripheral nuclei as in hallmark (Parker, et al., 2003). One of the first roles described for IGF-1 was its involvement in the proliferation and differentiation of satellite cells. In addition, IGF-1 expression in skeletal muscle extends the capacity to activate satellite cell proliferation (Charkravarthy, et al., 2000), increasing and prolonging the beneficial effects to the aging muscle.

Reviews in: Mourkioti and Rosenthal (2005), Trends in Immunology, Vol 26, No. 10

Hawke and Garry (2001), Journal of Applied Physiology, Vol 19, Page 534-551

Plasticity and therapeutic applications
Upon minimal stimulation, satellite cells in vitro or in vivo will undergo a myogenic differentiation program.

Unfortunately, it seems that transplanted satellite cells have a limited capacity for migration, and are only able to regenerate muscle in the region of the delivery site. As such systemic treatments or even the treatment of an entire muscle in this way is not possible. However, other cells in the body such as pericytes and hematopoietic stem cells have all been shown to be able to contribute to muscle repair in a similar manner to the endogenous satellite cell. The advantage of using these cell types for therapy in muscle diseases is that they can be systemically delivered, autonomously migrating to the site of injury. Particularly successful recently has been the delivery of mesoangioblast cells into the Golden Retriever dog model of Duchenne muscular dystrophy, which effectively cured the disease. However, the sample size used was relatively small and the study has since been criticized for a lack of appropriate controls for the use of immunosuppressive drugs. Recently, it has been reported that Pax7 expressing cells contribute to dermal wound repair by adopting a fibrotic phenotype through a Wnt/β-catenin mediated process. .

Regulation
Little is known of the regulation of satellite cells. Whilst together PAX3 and PAX7 currently form the definitive satellite markers, Pax genes are notoriously poor transcriptional activators. The dynamics of activation and quiesence and the induction of the myogenic program through the myogenic regulatory factors, Myf5, MyoD, myogenin, and MRF4 remains to be determined.

There is some research indicating that satellite cells are negatively regulated by a protein called myostatin. Increased levels of myostatin up-regulate a cyclin-dependent kinase inhibitor called p21 and thereby induce the differentiation of satellite cells.