Satellite cells
Encyclopedia
Myosatellite cells or satellite cells are small mononuclear progenitor cells with virtually no cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 found in mature muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

. They are found sandwiched between the basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...

 and sarcolemma
Sarcolemma
The sarcolemma is the cell membrane of a muscle cell . It consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils...

 (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
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

 niche, and are involved in the normal growth of muscle, as well as regeneration following injury or disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

.

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 myoblast
Myoblast
A myoblast is a type of embryonic progenitor cell that gives rise to muscle cells .The muscle cells can be skeletal muscle, smooth muscle, and cardiac muscle....

s before undergoing myogenic differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

.

Genetic markers of satellite cells

Satellite cells express a number of distinctive genetic markers. Current thinking is that all satellite cells express PAX7
PAX7
Paired box protein Pax-7 is a protein that in humans is encoded by the PAX7 gene.- Function :Pax-7 plays a role in neural crest development and gastrulation, and it is an important factor in the expression of neural crest markers such as Slug, Sox9, Sox10 and HNK-1....

 and PAX3
PAX3
PAX3 is a gene that belongs to the paired box family of transcription factors. This gene was formerly known as splotch. PAX3 has been identified with ear, eye and facial development. Mutations in it can cause Waardenburg syndrome types 1 and 3...



Activated satellite cells express myogenic transcription factors, such as Myf5
Myf5
Myf5 is a protein with a key role in regulating muscle differentiation.Myf5 belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include Myf5, MyoD , myogenin, and MRF4 ....

 and MyoD
MyoD
MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one...

. They also begin expressing muscle-specific filament proteins such as desmin
Desmin
Desmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...

 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
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...

 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
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...

. They become activated and re-enter the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

. 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 beneficaleffects 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
Mesoangioblast
A mesoangioblast is a mesenchymal-like cell, associated with the walls of the large vessels. Mesoangioblasts exhibit many similarities to pericytes found in the small vessels. Mesoangioblasts are relatively undifferentiated cells with the potential to progress down the endothelial or mesodermal...

 cells into the Golden Retriever
Golden Retriever
The Golden Retriever is a medium-sized breed of dog. They were historically developed as gundogs to retrieve shot waterfowl such as ducks and upland game birds during hunting and shooting parties. As such, they were bred to have a soft mouth to retrieve game undamaged and have an instinctive love...

 dog model of Duchenne muscular dystrophy
Duchenne muscular dystrophy
Duchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...

, 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 immunosupressive 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
PAX3
PAX3 is a gene that belongs to the paired box family of transcription factors. This gene was formerly known as splotch. PAX3 has been identified with ear, eye and facial development. Mutations in it can cause Waardenburg syndrome types 1 and 3...

 and PAX7
PAX7
Paired box protein Pax-7 is a protein that in humans is encoded by the PAX7 gene.- Function :Pax-7 plays a role in neural crest development and gastrulation, and it is an important factor in the expression of neural crest markers such as Slug, Sox9, Sox10 and HNK-1....

 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
Myf5
Myf5 is a protein with a key role in regulating muscle differentiation.Myf5 belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include Myf5, MyoD , myogenin, and MRF4 ....

, MyoD
MyoD
MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one...

, myogenin
Myogenin
Myogenin , also known as MYOG, is a gene.Myogenin is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development and repair...

, and MRF4 remains to be determined.

There is some research indicating that satellite cells are negatively regulated by a protein called myostatin
Myostatin
Myostatin is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor...

. Increased levels of myostatin up-regulate a cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...

 inhibitor called p21 and thereby induce the differentiation of satellite cells.

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