Skeletal muscle satellite cells

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Abstract:

Satellite cells are situated beneath the basal lamina and function as myogenic precursors for muscle growth and repair. Furthermore to anatomical location, satellite cells are characterized by markers such Pax7, CD34, M-cadherin and Myf5. They are activated from the quiescent state to fulfil their roles in maintenance, hypertrophy, and repair of adult muscle. The transcription factors have important roles in the early stage, development, myogenic differentiation of satellite cells during muscle repair, and as myogenic regulator. Also, in the adult skeletal muscle, the self-renewing myogenic cell is driven by asymmetrical cell division, where one daughter cell is committed to differentiation whereas the second continues to proliferate or becomes quiescent.

Recent studies have demonstrated that satellites cells can be used for therapeutics. But their efficiency is limited by the fact that it is impossible to deliver these cells to patients intravascular. Myoblasts do not contribute alone to muscle generation. Other potential sources include bone marrow-derived cells, fibroblasts and mesenchymal stem cells can play a crucial role in cell transplantation. [94] M. Sampaolesi, Y. Torrente and A. Innocenzi et al., Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts, Science 301 (2003) (5632), pp. 487-492. Full Text via CrossRef | View Record in Scopus | Cited B

Introduction

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Skeletal muscle is a very important tissue of the body. It is one of the three major muscle types, the others being cardiac and smooth muscle. Skeletal musculature is characterized by three main functions which are locomotors activity, postural behaviour, and breathing.

The skeletal muscles are responsible for skeleton movement and locomotion. Basically, muscles link two bones across its connecting joint but they can also link bone and soft tissue or two different soft tissues by tendons. When the muscle contracts, the linked tissues and body parts change their position, thereby creating movement, such as extending the arm or breathing or highly coordinated movements like swimming, skiing, or typing. The skeletal muscle is very important in the breathing motion. Breathing involves muscles of the thoracic wall such as the diaphragm which is a dome-shaped muscle that forms a partition between the thorax and the abdomen. The diaphragm contracts and increases the volume of thoracic cage allowing air flow into lungs. Furthermore, posture is very important for correct breathing, as a flexed or bent posture, it very complicated for the diaphragm to work correctly. In this way, the skeletal muscles function almost continuously to maintain the posture, making one tiny adjustment after another to keep the body upright. Skeletal muscles have muscle tone remaining partly contracted, which helps maintain body posture.

All of these muscle functions are essentials for an individual. However, sometimes, skeletal muscle is susceptible to injury after direct trauma (e.g., intensive physical activities, lacerations) or resulting from indirect causes such as neurological dysfunction or innate genetic defects. If they are unrepaired, these injuries can lead to the loss of muscle mass and locomotive deficiency. Also associated with cancer, HIV/Aids and ageing, the latter being the key factor in frailty in the elderly. This is the reason why old people might not have an independent lifestyle anymore resulting in a lot of problems in their economic and social development. The muscle health is of primary importance for an individual.

But, in healthy individuals, skeletal muscle has an amazing ability to regenerate. This is due to its accompanying muscle stem cells known as satellite cells. These cells reside under the basal lamina of the muscle fibre they are associated with. The cells are usually quiescent, but upon injury, they become activated to reinforce existing fibres or to replace damaged fibres. In recent years, inroads into the understanding of satellite cell biology have been made. This has provided the opportunity to envisage for the first time satellite cell-based therapies for so far incurable forms of muscle diseases.

In this report, I will explain the molecular regulation of the muscle fibers satellite cells biology. In the first part, I will talk about the major functions of satellite cell such as to provide myonuclei, to produce materials for export, the adaptive response after prolonged exercises and finally to repair damage. In the second part, I will argue about the origin of the satellite cells. In the third part, I will focus in more details on the mechanisms of satellites cells their role in damaged muscle. In the fourth part, I will discuss self renewal and, in parallel, what signals allow self-renewal of satellite cells. In the fifth part, I will talk about recent advances revealing the development of therapeutic strategies ,with satellites cells and other types cells, that may extenuate some of the pathological conditions associated with poor muscle regenerative capacity, such as the one observed in muscular dystrophy patients.

Satellite Cell Functions

Myonuclear Production

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Satellite cells have an important role in postnatal skeletal muscle. Their function lies of elongated multinuclear fibres that appear from cell fusion. So, the postnatal growth period is a rise in the DNA of myofibres (Moss and Leblond, 1971). Earlier the discovery of satellite cells, it was understood that the capacity to divide is missed when a myoblast nucleus is integrated into the syncytium of a myofibre (Stockdale and Holtzer, 1961). First researches demonstrated that the postnatal growth period is an augmentation in the DNA of the myofibres (Enesco and Puddy, 1964). This increase in the number of myonuclei is done in postnatal muscle was demonstrated by the radioautographic by Moss and Leblond (1971) exploiting timed injections of [3H]thymidine adjacent muscle fibers. The time which is necessary for fusion of a cell after injection of label is 18 h, when 5% of nuclei fuse with fibers. After 48 h, the half of labeled nuclei from injection is within myofibers. This revealed those division satellite cells and the fusion of their daughter cells after a mitotic division, caused to the rise in the myonuclear DNA within the myofibre syncytia (Moss and Leblond, 1971).

Also, satellite cells compose approximately 30% of the muscle nuclei in the neonate, and diminish with age to approximately 4% in the adult and 2% in the senile mouse. The reduction in the number of satellite cells with aging is the consequence of an increase in myonuclei and a decrease in number of satellite cells (Snow, 1977).

Synthetic Functions

Actually, myonuclear production is poor understood. It just recognizes in the function of satellite cells in normal muscles. Nevertheless, satellite cells in immature muscles have a correctly developed Golgi and endoplasmic reticulum. This can suggest that satellite cells possess other functions.

In young muscles, satellite cells have a superior volume of cytoplasm than cells of mature muscles. The important organelles of immature cells are rough endoplasmic reticulum (rER) and the golgi. The rER cisternae of cells growing muscles are generally large but reduced as the growth and the Golgi is greatly developed. When age enhances, they observe a reduction in the volume of cytoplasm and in the organelles (Schultz 1976). These changes suggest that satellite cells in immature muscles are more involved in synthetic work than those in mature muscles.

In vitro studies indicate that satellite cells secrete some products during postanal period. For example, Le Moigne et al. (1990) found that the extracellular matrix proteins laminin and fibronectin are produced by satellite cells. Using immunoreactivity or in situ hybridization, other products associated with satellite cells are fibroblast growth factors (FGF) and phoshphoglycerate mutase (Castella-Escola et al., 1990). But the definite satellites roles which have in muscle and satellite cell development must be determined. Increased growth or rise activity causes an activation of satellite cells and an increase in cytoplasmic volume and organellar content. These observations indicate that young satellite cells have the appropriate supplement of organelles to produce materials.

Roles during Muscle Adaptive Responses

After the end of the postnatal growth period, satellite cells are quiescent and do not have other mitotic divisions (Schultz et al., 1978). The first response of muscle in an adult is the reinforcement of existing fibres via deposition of more protein. It has been established that intense exercises enhance protein synthesis and that protein synthesis remains elevated for approximately 24 h. Increased protein synthesis indicates that myonuclei which exits in muscle fibres have the competency to quickly respond to intense exercises by enhancing their translational capacity.

Nevertheless, when myofibers increase the demand, satellite cells are activated and then re-enter the proliferative state. Prolonged exercise programs require activation and proliferation of satellite cells. The response of satellite cells to amplify functional demand is rapid. Hypertrophy of myofibers is composed by satellite cell divisions and fusions in order to increase the complement of myonuclei (Rosenblatt et al., 1992). Sometines in hypertrophy, satellite cells are induced not only to supply additional nuclei to the enlarging fibers but also to form new fibers. In effect, McCormick and Schultz, (1992) suggest that the new fibers in the extrafascicular space of the avian anterior latissimus dorsi muscle (ALD) is the consequence of the proliferation and fusion of myogenic cells derived from satellite cells. Also, in each exercise, the increased proliferative of satellite cells can not be distinguished from myofiber damage because satellite cells are associated with muscle fibers in stages of degeneration or regeneration (Snow, 1990). Their association with damaged fibers indicate that changements in proliferative activity allow regeneration or repair response.

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Satellite cell fusion could be involved in changes in myofibers induced by increased activity, or modifications in neural. For example, Eisenberg and Jacobs (1990) suggest that alterations in myosin isoform expression are needed to the addition of nuclei to expression of new genes. McCormick and Schultz (1990) showed the expression of ventricular-like embryonic myosin in fibers of stretched chicken ALD muscle is not dependent on the presence of newly fused myonuclei. Likewise, Rosenblatt and Parry (1992) inhibited satellite cell proliferation and fusion by irradiation and found expression of new myosin isoform expression in hypertrophying muscle which is the same that seen in nonirradiated muscles. These results suggest that satellite cell fusion is not an obligatory step during modifications in gene expression associated with adaptive responses in skeletal muscle fibers.

Satellite cell proliferation and fusion leading to an increased number of myonuclei may be related to stabilization of the transformed state (Schuttz and Darr, 1990). Alterations in myofiber volume implicated by altered activity levels may change the size of the cytoplasmic domain associated with each nucleus.

Roles during Damaged Muscle: repair and regeneration

The fourth main function of satellite cells in the skeletal muscle is to repair damage engaged by myofibres. After damage, satellite cells are activated into a regeneration response that repairs or replaces myofibres.

Satellite quiescent cells may be activated by growth factors and then express myogenic regulatory factors likewise than muscle precursor cells do during skeletal muscle development. Then, the satellite cells proliferate and fuse with each others to form myotubes showing in the figure 1.

Blaveri et al. (1999) has showed that clones of satellite cells are adequate to give rise to new muscle and to self-renew which will give rise to more satellite cells in vivo. This demonstrated well that the satellite cells have a role in the regeneration of muscle. These cells are also maintained within the host muscle as long lived precursor cells, allow to give rise to new muscle when the muscle is injured (Gross and Morgan, 1999).

  1. Normal muscle fibre with myonuclei and a satellite cell.
  2. Damaged muscle fibre. The satellite cell has become activated and proliferated in response to the damaged fibre.
  3. Muscle precursor cells derived from the satellite cell have fused together to repair the damaged muscle fibre.
  4. Regenerated muscle fibre with a new satellite cell.

Developmental Origins of Satellite Cells

Somitic Origin

The skeletal muscles in the vertebrate embryo can be determined by three major embryonic groups: epaxial body muscle, hypaxial body muscle and head muscle. Body muscle (i.e. trunk and limb muscle) is derived from the somites during embryogenesis, whereas head muscle develops from three sources: somites, paraxial head mesoderm and prechordal mesoderm. Gros et al. (2005) show in particular, chick somites electroporation of green fluorescent protein, that embryonic muscle progenitor, which is implicated, during embryonic and fetal life, in the growth of trunk muscles and satellite cells, have a common origin, the dermomyotome.

Thereby, somites differentiate into dermomyotome, an epithelial structure located in the dorsal part of the somite, then in sclerotome, a mesenchyme located in the ventral part. Mesodermal cells become skeletal muscle precursors within the nascent myotome. Myogenic progenitor cells (mpc) continue to be generated from the dermomyotome (Ben-Yair et al., 2003). They contribute to the myotome and also migrate from the myotomal lips to go the muscles of the limb and diaphragm fields.

Not all satellite cells are of somitic origin. Some head muscles are unique, they do not come from somites but from prechordal mesoderm and have a distinct genetic network controlling their formation (Tzahor et al., 2003).

The molecular signals that regulate the entry of embryonic cells into quiescence are not well determined. But recent reports have highlighted the importance of Notch signalling in satellite cell ontogenesis (see part V.Self-Renewal and Heterogeneity of Satellite Cells). B. Markers of quiescent cells:

The anatomical definition of a satellite cell is that all cells located beneath the basal lamina of a myofibre are satellite cells, independant of their function or gene expression. Recent molecular markers have allowed the reliable identification of satellite cells at the light microscope level (Figure2).

Recent studies suggest that Pax3+/Pax7+ progenitors, which are originating in the embryonic somite, can be inductors of satellite cells in adult muscle (Kassar-Duchossoy et al., 2005). Indeed, mpc that expresses Pax3 and Pax7, originate from the dermomyotome, and are maintained during embryogenesis within the developing skeletal muscles (Gros et al., 2005).

The quiescent satellite cells in the mouse are positive for the expression of Pax7 (transcription factor), CD34 (saliomucin), M-cadherin (a calcium-dependent cell adhesion protein), and Myf5 (transcription factor).

In normal mature muscle, satellite cells are quiescent and express Pax7.

In effect, Zammit et al. (2004) reveal that the transcription factor Pax7 is expressed in cultures of satellite cell-derived myoblasts in adult muscle. In the same way, electron microscopic analysis showed an absence of satellite cells in Pax7-/- skeletal muscle.

Whereas this gene is not induced in the formation and development of pre-natal muscles, Pax7 is the most useful current marker for identifying quiescent satellite cells during post-natal life (Seale et al., 2000)(Figure2).

Also, markers such as CD34 are not specific to satellite cells in human muscle but are useful markers on isolated myofibres because distinguishing satellite cells from other positive cells (e.g., endothelial cells) on muscle is more difficult. Some analysis require not only the satellite cell marker but also co-immunostaining to identify the basal lamina (Beauchamp et al., 2000) (see Figure2).

Secondly, Irintchev et al. (1994) have showed that the expression of M-cadherin (Mcad) plays a crucial role in quiescence. By immunofluorescence, they demonstrate that Mcad positive cells in normal and denervated muscles did not assimilate bromodeoxyuridine within 24 hr after injection in vivo, suggesting that Mcad is expressed in quiescent satellite cells. Also, studies indicate that other cell adhesion molecules like vascular adhesion molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) are markers of quiescent satellite cells. The role of these adhesion molecules is unclear but together (NCAM, VCAM-1, and M-cadherin) may function in the adhesion of the satellite cell to the basal lamina of the myofiber and contribute in the migratory capacity of this cell population in response to stimuli (Seale et al. 2004).

In addition, the Myf5 locus is active in quiescent satellite cells in using the Myf 5nlacZ/1 mouse and transgenic mice lines. But whereas wild-type Myf5 mRNA can be identified in quiescent satellite cells there is no definitive evidence that the protein itself is present. The Myf5nlacZ/1 mouse also provides a marker for the contribution of donor cells to the satellite cell after transplantation (Beauchamp et al., 2000) (See Table1).

Roles during Damaged Muscle

Activation from quiescence

In the adult, satellite cells are in a niche near to the sarcolemma muscle fibers and the basal lamina and are quiescent. Following injury which induces stress, these cells become activated resulting in modifications in gene expression.

The activation trigger of the satellite cells is unknown but recently a lot of mechanisms have been discovered. Recent studies suggest that satellite cells may be capable of producing growth factors such as VEGF, FGF, HGF or TNF- a.

In the first potential mechanism, fiber damage stimulates the production of Nitric oxide (NO) by the enzyme, Nitric oxide synthase (NOS) triggering the release of hepatocyte growth factor (HGF), and this is associated with its receptor c-Met which is an early gene in activation of satellite cells (Wozniak et al., 2007).

Also, nitric oxide induces expression of Follistatin, a fusigenic secreted molecule, which inhibits Myostatin (expressed by quiescent cells a negative regulator of myogenesis). Thus it maybe contributes to active the satellite cells (Pisconti et al., 2006).

Shu et al. (2002) has shown a second mechanism that vascular endothelial growth factor (VEGF) binding to VEGF receptor 2 which induces endothelial cell growth by protein kinase C, and activates of sphingosine kinase 1 which produces the formation of Sphingosine-1-phosphate (S1P). Then S1P, which allows the entrance in the cell cycle, activate (ERK)-MAPK pathway resulting in cell division.

Moreover, because hepatocyte growth factor (HGF) and fibroblast growth factor (FGF) bind a tyrosine kinase type receptor, also S1P will stimulate ERK-MAPK (Yablonka-Reuveni et al., 1999).

In addition to growth factors, tumor necrosis alpha (TNF-a) which is a cytokine, has been suggest to be able to activate satellite cells. In effect, injection of TNF-{alpha} increases BrdU incorporation by satellite cells in muscles of adult mice (Li, 2003).

Jones et al. (2005) established that the p38a/B MAPK signalling, which is induced by FGF, HGF and VEGF might be required for satellite cell activation and the regulation of the quiescent state of satellite cells. Indeed, analysis of p38a mutant showed that, in cultured myoblasts, p38a removal induces a delay in the exit of cell-cycle and modifies expression of cell-cycle regulators. Also, p38a mutants revealed increased myoblasts proliferation in the neonatal period in consequence of the continuous proliferation and the delay in growth arrest (Perdiguero et al., 2007).

Markers of actived Satellite Cells

To accomplish their role in muscle maintenance, hypertrophy, and repair, satellite cells must first be activated from this quiescent state to produce myoblast progeny (Wozniak et al., 2005). Satellite cell-derived myoblasts are characterized by the same myogenic markers as myoblasts derived from developmental stage.

Myf5. Then, they begin to divide, expressing additional genes from cycling cells such as PCNA. Myogenin marks the beginning of myogenic differentiation (Yablonka-Reuveni and Rivera, 1994) together with a variety of regulatory and structural muscle genes of skeletal muscle myocytes. The pattern of Mrf4 expression during satellite cell myogenesis is less understood because it can be expressed either after, or prior to, initiation of myogenin expression (Smith et al., 1993).

Molecular regulation of satellite cell-derived myoblasts proliferation and differentiation

The efficiency of satellite cell derived myogenic depends on the expression of Pax genes (Pax1-9) and myogenic regulatory factors (MRF) (such as MyoD, Myf5, myogenin, MRF4). Activation and suppression of Pax3/7 and MRF is necessary for the development of skeletal myoblasts through myogenesis.

Pax Family

During embryogenesis, the family of transcription factors (Pax1-9) has crucial functions in the regulating of development and the differentiation of satellite cell and their daughter myogenic precursors.

Electron microscopic analysis and cell culture show removal of satellite cells in Pax7-/- skeletal muscle. These results indicate an essential role for Pax7 in the satellite cell myogenic lineage functioning upstream of the MyoD family (Seale et al., 2000). In addition, few satellite cells with Pax7 deficiency survive but these cells arrest and die at the moment of entering mitosis. Furthermore, fiber diameters are decreased and also Pax7-/- muscles are reduced in size because the fibers contain only the half of the normal number of nuclei. Together, these data confirm that Pax7 play an important role in regulating the myogenic satellite cells (Kuang et al., 2007).

Pax3 is detected after activation in myoblasts and so, is also expressed in quiescent satellite cells. The roles that play Pax3 in muscle regeneration are not well understood, after that Pax3-null mouse dies in utero.

Pax3 and Pax7 have equivalent roles in the activation of myogenic genes but only Pax7 possess anti-apoptotic function (Relaix et al., 2006).

Analysis of mutations in mice indicates that Pax3 and Pax 7 proteins are essential for the development of a number of distinct cell lineages and suggest to have only redundant roles in myogenesis although both are structurally similar (Seale et al., 2000).

These data, together, suggest that Pax3 play a role in the migratory phase of the lineage whereas Pax7 is required to achieve myogenic specification of satellite cells.

Recent studies showed the considerable role of Pax proteins regulation during adult myogenesis.

During satellite cell activation, Pax3 can be regulated by monoubiquitination and proteasomal degradation. Boutet et al. (2007) argue that control of Pax3 degradation is an important step for the progression of myogenic pathway. In effect, maintained mutant Pax3 expression inhibited myogenic differentiation (Boutet et al., 2007).

Moreover, regulation of MyoD allows to Pax7 to induce myoblast proliferation and to delay their differentiation. In parallel, myogenin directly affects Pax7 by down-regulating Pax7 expression during differentiation (Olguin et al., 2004).

Myogenic Regulatory Factors

In contrast with Pax3/7 genes, MyoD and Myf5 have clearly roles defined.

MyoD allows the differentiation of skeletal myoblasts in considering that Myf5 regulates their proliferation level and homeostasis.

During embryogenesis, Myf5 and MyoD each compensate for the lack of the each other, but they cannot compensate for each other in the adult state (Gayraud-Morel et al., 2007). Additionally, Myf5 deficiency leads to a decrease in myoblasts and to a lack of MyoD. This induces self-renewal rather than myogenic differentiation.

The first targeted mutations of the Myf5/MRF4 locus showed that the loss of these genes in mice leads to defects in primary myotome formation, thus the importance of Myf5 in the formation of myotome. Gayraud-Morel et al. (2007) suggested that mutant mice show signs of repeated regeneration and more adipose infiltration in the muscle tissue after a freeze injury. Myf5 supports efficient regeneration by giving myoblast regeneration. Also, compound Myf5-null/mdx mutants show regeneration and an aggravation of the dystrophic phenotype, owing to satellite cells lacking proliferative potential (mdx mice lack functional dystrophin and are thus an animal model of human Duchenne muscular dystrophy).

After those myogenic cells have proliferated, skeletal-muscle development entails the differentiation and fusion of progenitors to form multinucleated myotubes and myofibres. Smith et al. (1994) demonstrated that Myogenin is activated during differentiation. Myogenin expression is detected in RNA from a cell culture, 24 h before myoblast fusion is detected. So, Myogenin expression is induced just before myotubes fusion which is the differentiation. Myogenin is required and necessary for the formation of myotubes and fibers showing by Figure 4.

Satellite cells are quiescent in normal adult muscle and can be activated by injury. Only CD34, Pax7, and Myf5/b-gal are expressed in this state. Once activated, satellite cells divide to produce myoblasts and then proliferate where MyoD is rapidly express. Later, Myogenin involves committing satellite cells derived myoblasts to differentiation and fusing to form myotubes, which then mature into myofibers. In the later stage of differentiation, MLC3F-tg is expressed, which is specific of structural muscle genes such as skeletal muscle actin and MyHC (marker of sarcomeric assembly).

Self-renewal and heterogeneity of Satellite Cell Populations

Following activation, the satellite cell leaves their niche and coexpress Pax7 and MyoD. The skeletal myoblasts, after the satellites cells, is submitted to multiple divisions. Most of them will downregulate Pax7 but will express myogenin and will differentiate to fuse and form multinucleated myofibers (Figure 4).

In contrast, few cells maintain Pax7 expression, lose MyoD and retire from differentiation. Kuang et al. (2007) showed that few cells are the self-renewing cells that will return to quiescence and occupy the satellite cell compartment. They used Myf5 mice, which demonstrated that muscle satellite cells are a heterogeneous population of committed progenitors and stem cells. In fact, some satellite cells, which never expressed Myf5, asymmetrically divide, and increase Myf5+ve daughter committed to myogenesis as a self-renewing Myf5 negative daughter (Figure 5).

During regeneration, satellite stem (Myf5YFP-ve) cells can give rise to a self-renewing daughter (blue arrow). Also, Myf5-ve stem cells are able to give rise to uncommitted progenitors which will participate in regeneration of the tissue (grey arrow). In other side, Myf5-ve gives an increase of the committed (Myf5YFP+ve) daughter. Committed cells become activated, proliferate and Myf5+ve cycling myoblasts mainly differentiate and contribute to new fiber formation.Some Myf5+ve myoblasts can also downregulate MyoD and return to quiescence (red arrow).

In dividing skeletal myoblasts, Conboy et al. (2007) has demonstrated the co-segregation of template DNA strands by using pulse-chase labelling of stem cells with halogenated thymidine analogs. Indeed, stem cells which divide asymmetrically, maintain the oldest DNA strand in limiting mutations in self-renewing.

Lansdorp (2007) explain another model, where asymmetric cell divisions are caused by epigenetic variations between sisters chromatids and that the maintenance of self-renewal properties is induced by the co-segregation the DNA strands which have the more active stem cell genes.

Additionally, Notch signalling forms a regulatory network which may direct self-renewing the cells. Also, it suppresses early activation of MyoD and thus up-regulates proliferative expansion of myoblast progeny. A transformation from Notch to canonical Wnt signalling, acts as a switch to suppress proliferation and initiates terminal differentiation in myoblasts (Figure 6).

Brack et al. (2007) reveals the participation of Notch and Wnt signaling during regeneration in vivo and confirms a role for Wnt signaling in inducing differentiation. They also describe the involvement of Notch in regulating proliferative expansion of myoblasts in adult myogenesis, but implicate a conversion from Notch to canonical Wnt signalling as a mediator for the switch between myoblast proliferation and induction of differentiation in these progenitors (Figure 6).

Finally, Numb, an inhibitor of Notch signalling, influences cell destiny choices by promoting differentiation (Conboy et al., 2003).

After muscle injury, nitric oxide is released and active growth factor which stimulates ERK-MAPK pathway. This pathway implicated in the satellite cells proliferation is one among others explicated before. When the satellite cells proliferate thanks to many transcriptions factors, a dilemma is present. Either the satellite cells self-renewing either the satellite cells differentiate and fuse to form new myotubes. The replenish cells can be regulate by Notch which it also implicates in Wnt signalling.

Analysis of the use of satellite cells in cellular therapies for muscle disease

Satellite cells for stem cell-based therapies

Satellite cells are candidates for stem cells- based therapies. In effect, they possess a lot of advantages but also some disadvantages. Firstly, satellites cells can be identified in a certain way. Satellite cells are distinguished by anatomical localization, near to a myofiber under the basal lamina allowing the self-renewal of satellite cells after transplantation. Secondly, satellite cells can be derived easily, without complicated procedures, from human skeletal muscle biopsies. Satellite cells express also, a large number of markers see previously. In addition, large number of satellite cells can be collected after transplantation in view of the fact that skeletal muscle tissue is very numerous in the human. Thirdly, recent studies have established the efficiency of self renewing satellite cells after transplantation. This capacity allows long term function of the transplanted cells. Finally, satellite cell-derived myoblasts have been already used in clinical trials to treat muscular dystrophies and cardiac repair.

However, satellite cells are only appropriate for intramuscular injections which are a procedure less tolerable by patients. Like the intramuscular migration is slow, myoblasts might be injected in different area in muscle with a high density. Recent studies suggest that matrix metalloproteases treatment will allow a better migration of transplanted myoblasts (Bedair et al. 2007). The major issues for muscle stem cell transplantation in the context of Duchenne muscular dystrophy remain that the patient must be treat by an immunosuppressive treatment and that the transplanted stem cells do not home to the heart, which is also affected by the lack of dystrophin (which is the component of a complex of proteins important for membrane stability and force transduction from muscle ?bers).

Li et al. (2006) indicate that using of viral vectors to stably transduce myogenic stem cells with therapeutic genes. Direct intramuscular injection of lentiviral vectors, driving a mini-dystrophin-eGFP fusion transgene, into neonatal mdx mice causes to dystrophin-eGFP expression 2 years after injection and to morphological and physiological improvement. Satellite cells can also be stably transduced and thus contribute to long-term amelioration.

Moreover, when allogenic myoblasts are used for transplantation, there is a possible immune rejection. To remedy at this problem, Skuk et al. (2007) proposed that immunosuppressants such as tacrolimus could reduce the rejection

Other cells types for therapies

Although satellite cells are the most obvious sources of donor cells for transplantation to treat skeletal muscle diseases, recent studies suggest that they are not the only sources of myoblasts in skeletal muscle. Other potential sources include bone marrow-derived cells and mesenchymal stem cells[94] M. Sampaolesi, Y. Torrente and A. Innocenzi et al., Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts, Science 301 (2003) (5632), pp. 487-492. Full Text via CrossRef | View Record in Scopus | Cited B can be contribute to muscle generation if necessary. By the isolation of bone marrow cells, researchers identify an alternative source of myogenic cells but also develop a systemic treatment for DMD based. The use of a bone marrow transfusion will capable the transfer of a therapeutic quantity of myogenic precursors from the blood to the myofibers. Ferrari et al. (2001) revealed the efficiency of bone marrow transplantation to induce the expression of donor dystrophin in a dystrophin-deficient mouse can be negligible because only 0.25% of the myofibers expressed dystrophin during each mouse. In addition, they also found that bone marrow-derived progenitors reveal slower differentiation kinetics when compared to satellite cells, indicating that the myogenic commitment in these cells could involve a multi-step process.

Some researches indicate that fibroblasts can differentiate into myoblasts. Goldring et al. (2002) show that normal murine dermal fibroblasts inserted into the muscles of mdx mice contributed to new myofiber formation and restored the expression of dystrophin. They proved that the lectin galectin-1 is involved in the conversion of dermal fibroblasts into a myogenic lineage. They also reported that exposure of clones of dermal fibroblasts to this lectin resulted in 100% conversion of the cells. Galectin-1 did not, however, induce myogenic conversion of murine muscle-derived fibroblasts.

Moreover, Sampaolesi et al. (2006) demonstrated with the adult mesoangioblast, a vessel-derived stem cell that can be efficiently transplanted by intra-arterial delivery. But these cells resulted in a clinical amelioration and preservation of motility only in the golden retriever dog model of Duchenne muscular dystrophy. Now, it just remains to do the first clinical trials in humans.

Conclusions

The discovery of the satellite cell in 1961 provided the obvious candidate for the source of new muscle growth and repair. It remains the myogenic progenitor of skeletal muscle. Intensive researches have uncovered many signalling molecules involved in the regulation of quiescence, activation, self-renewal, and differentiation. But how these signals are interpreted by intracellular machinery are only beginning to be understood. For example, it is unknown what mechanisms initiate and maintain Pax7 expression, and the direct effectors of Pax7 activity are still largely unknown. It is evident that the complexity exists within the networks that regulate myogenesis. Examples from Peter Rigby's laboratory have used differential enhancers and promoters of the Myf5/MRF4 locus to coordinate gene expression in precisely defined progenitor cell populations and at different times. However, some mechanism about how satellite cells can renew has been clarified. In effect, satellite cells are a heterogeneous population which is composed of stem cells and committed myogenic progenitors. So, satellites cells can induce self-renewing stem cells or differentiated myogenic cells by asymmetric division. This discovers open news avenues for therapeutic treatment of neuromuscular diseases.

A large amount of research is directed at exploiting the therapeutic potential of muscle stem cells for the treatment of degenerative diseases such as muscular dystrophies. For satellite cells to be successfully applied to cell-based regenerative medicine in skeletal muscle repair, many questions remain to be answered regarding the molecular mechanisms that control their proliferation, self-renewal and differentiation. Each of these steps is regulated by extrinsic and intrinsic signalling pathways. One challenge in future studies is to have a comprehensive understanding of how various extrinsic signalling mechanisms coordinate to regulate the gene expression and epigenetic programs that control the lineage progression of satellite cells. There are many competitions associated with the use of cell transplantation to improve muscle regeneration and repair. It is clear that the identification of the best cell type such includes bone marrow-derived cells and mesenchymal stem cells or fibroblasts, will be the major determinants in the success of this type of research.