the muscle stem cell niche: regulation of satellite cells during
TRANSCRIPT
The Muscle Stem Cell Niche: Regulation of Satellite CellsDuring Regeneration
Kristel J.M. Boonen, M.Sc.,1 and Mark J. Post, M.D., Ph.D.1,2
Satellite cells are considered to be adult skeletal muscle stem cells. Their ability to regenerate large muscle defectsis highly dependent on their specific niche. When these cells are cultured in vitro, the loss of this niche leads to aloss of proliferative capacity and defective regeneration when implanted back into a muscle defect. The mostimportant aspects of the niche will be discussed—in particular, the basement membrane, the niche’s mechanicalproperties, its supporting cells, and the influence these features have on satellite cell activation, proliferation, anddifferentiation. Understanding more about the control of these satellite cell activities by the niche will facilitatetheir recruitment and effective deployment for regenerative medicine.
Introduction
Tissue-resident adult stem cells play a crucial role inthe maintenance of tissues that are subject to daily wear
and tear. They have been identified in many different posi-tions in the body, including bone marrow, brain, liver, intes-tine, and heart.1–5 In general, a small population of stem cellsis present in a highly specific environment that consists ofextracellular matrix (ECM) and different types of surroundingcells, including organ-specific and mesenchymal cells.6 As theneed and capacity for repair differs widely among tissues, theinteraction of stem cells with their direct environment hastissue-specific characteristics in addition to common features.The presumed specificity of the environment has formed thebasis for the ‘‘niche’’ concept in which structural and bio-chemical cues importantly determine stem cell behavior. As acommon feature, niches contain a basement membrane (BM)as one of their most important components.7 The key questiontherefore is how such a common feature confers specificity onthe process of stem cell recruitment.
Adult stem cells have the capability to self-renew, with aseemingly indefinite number of cell doublings. While self-renewal is functional for regenerative purposes, it is clearthat proliferation and differentiation of stem cells need to betightly regulated to prevent uncontrolled growth. An im-portant part of this regulation is probably provided by thestem cell niche, which exerts this control through guidance ofsignals by the re-organizing ECM.3,7–9
Skeletal muscle is a type of tissue that typically experi-ences bouts of high levels of regeneration and repair and forthis reason houses stem cells. There has been much debateabout which cell type qualifies as the muscle adult stem cell,
but the most prevalent notion is that the satellite cell ora subset of satellite cells most likely assumes this role.10–16
The anatomical location of the satellite cell (in betweenthe sarcolemma and the BM; Fig. 1), its capability of self-renewal,15,17–19 its regenerative capacity in vivo,15 and plas-ticity in vitro12,20–22 show that the satellite cell possesses allthe requisite characteristics of a skeletal muscle stem cell.23 Incase of skeletal muscle injury or another type of stimulus,satellite cells are activated and become proliferating myo-blasts. If necessary, they migrate to the designated site wherethey differentiate and fuse with existing or damaged fibers orform new fibers by fusing with other myoblasts.
However, an important and poorly understood limitationof the satellite cell is its in vitro proliferative capacity: Afterisolation, satellite cells can only divide a small number oftimes.24 On the other hand, in vivo, a small amount of tissue-resident satellite cells is sufficient to regenerate large parts ofmuscle tissue.15,25 The inability to recapitulate the prolifera-tive capacity in vitro is probably due to loss of the highlyspecific niche that normally surrounds these cells.26
Satellite cells are commonly defined according to theiranatomical location.27 However, they have been shown to bea heterogeneous population according to their expression ofmolecular markers, suggesting varying roles for the differentsubpopulations in the regenerative process.28–36 A number ofmarkers have been proposed that should distinguish theentire population such as M-cadherin,29 CD34,33 c-met,29 andPax7.37 Evidence exists for the presence of a small stem cell–like population within the satellite cell compartment,15,19,38
indicated by the observation that some myoblasts do surviveafter injection into injured host muscle and are capable ofrobust regeneration, albeit only at the site of injection.39
1Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.2Department of Physiology, CARIM, Maastricht University, Maastricht, The Netherlands.
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Stem cells are the ideal candidates to boost regenerationafter extensive injury or to substitute a defective repair mech-anism. The oldest regenerative therapy proposed is myoblasttransfer therapy (MTT)40 in which isolated myoblasts arecultured in vitro and then injected into muscles of compro-mised living recipients.41 The first MTT studies focused on therestoration of dystrophic muscle in a mouse (mdx) model ofDuchenne muscular dystrophy (DMD)39,42,43 and later on inDMD patients.44–48 Unfortunately, most injected myoblasts donot even survive the first hour after injection and do not mi-grate from the site of injection, resulting in failure to restorefunction.39,43,49,50 When myoblasts are injected in a fibrin clot,51
survival does not improve. However, when satellite cells areisolated without enzymatic digestion of the muscle fiber15 andinjected without further culturing in vitro, regeneration ofdamaged muscles is successful.15,25,52,53
More recently, tissue engineering using primary cells54–60
or cell lines55,61–63 and standard matrices such as collagenand poly (glycolic acid) (PGA)=poly-L-lactic acid (PLLA) hasbeen studied for regenerative purposes, but with limitedsuccess.64–68 However, implantation of myoblasts seeded inan decellularized muscle matrix gives long-term repair.65
Current studies on the optimal biochemical and physicalconditions of the scaffolds to support myoblast survival anddifferentiation are aimed at improving this therapeutic plat-form. The studies are based on the premise that the environ-ment should resemble the natural recipient environment asmuch as possible to fully support differentiation and matu-ration of myoblasts into adult skeletal muscle.
Finally, understanding these niche principles could alsofacilitate stimulating satellite cells in situ for skeletal muscleregeneration.
FIG. 1. (A) Location of the satellite cell in between the sarcolemma and the BM. (B) Close-up of the coupling of the BM tothe satellite cell plasma membrane. (C) Cross section of B. Color images available online at www.liebertonline.com=ten.
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In this review, we provide an integrated view on the roleof the most important aspects of the satellite cell niche (theBM, mechanical properties, and supporting cells) and theirputative pathways to control stem (satellite) cell activation,proliferation, and migration in regenerating skeletal muscle(Fig. 2).
Satellite Cell Niche
A stem cell niche is commonly defined as ‘‘a specificlocation in a tissue where stem cells can reside for an in-definite period of time and produce progeny cells while self-renewing.’’69 Most niches contain a BM, to which the stemcells attach.7 At either site of the BM, permanent so-calledsupporting cells can be localized that are of importance tostem cell functioning.7 The satellite cell niche indeed containsa BM and muscle fibers,10 and=or endothelial cells70 are closeby and could function as supporting cells. However, al-though they have been shown to have an effect on prolifer-ation of myoblasts in vitro, endothelial cells have not beenshown to be in direct contact with satellite cells. In most stemcell niches (e.g., in the intestine), the supporting cells aresmall cells that are located at the opposite site of the BM, butcases exist (e.g., in the testis, reviewed by Wong et al.71) inwhich stem cells are supported by big cells located at thesame site of the BM. Therefore, the muscle fiber is the most
promising candidate as the satellite cell niche’s supportingcell. Alternatively, in the Drosophila midgut, stem cell nicheswere described that do not rely on supporting cells for theirfunction,72 opening the possibility that the satellite cell nicheexists without any supporting cells. This hypothesis is re-inforced by the fact that satellite cells with or without theparent fiber regenerate defects similarly after transplanta-tion, as long as the isolation methods are optimal.15
Another prerequisite of a stem cell niche is that when it isdepleted of stem cells, it should persist and be able to housenew stem cells.73 Bone marrow stem cells, for example, canenter and leave the circulation to occupy empty niches in aprocess called homing (reviewed by Whetton and Graham74).Not only satellite cells25,30 but also bone marrow cells30,70,73
have been shown to be able to occupy empty satellite cellniches, satisfying also this requirement.
When the satellite cell niche is compared to niches in othercommon stem cell systems, such as skin and intestine, themost obvious difference is that satellite cells in their niche arequiescent, whereas in most systems stem cells are constantlyactive to replace cells that are lost due to daily wear and tear.Usually, an intermediate cell called transit-amplifying (TA)cell takes care of actual expansion, whereas the stem cell onlycontinuously replenishes this TA population. In the intestine,for example, stem cells at the bottom of crypts constantlydivide to give rise to TA cells that move up and differentiate
FIG. 2. Overview of the most important components of the satellite cell niche and their influence on activation, prolifer-ation, and differentiation. Color images available online at www.liebertonline.com=ten.
REGULATION OF SATELLITE CELLS BY STEM CELL NICHE 421
to ensure a steady flow of cells that are shed at the surface(reviewed by Yen and Wright75). However, in other tissues,niches do exist that contain quiescent stem cells. In the heart,for example, cardiac stem cells (CSCs) are thought to takecare of regeneration (reviewed by Leri et al.5). It is hypothe-sized that CSCs are quiescent cells, surrounded by a BM, thatgive rise to a TA population after activation, which is thenresponsible for actual repair.5
Possibly, such a TA population also exists in the musclestem cell system.36 It has been shown that satellite cells are aheterogeneous population containing a small stem cellcompartment,10,28,29,36,76 which could mean that the rest ofthe satellite cells should be perceived as TA cells. Evidencefor this theory comes from elegant studies showing a hier-archical lineage relationship of satellite cells.77,78 Alter-natively, all satellite cells should be considered TA cells thatdescend from a common precursor stem cell located else-where, for example, in the interstitial spaces of skeletalmuscle.36,78 However, observations that satellite cells self-renew15,18,79 and regenerate muscle15 clearly show that theyare more than just TA cells.23
Basement Membrane
The BM is a specialized sheet of connective tissue. Its mostimportant constituents are type IV collagen, laminin, andheparan sulfate carrying proteoglycans (HSPGs). A lamininnetwork faces the muscle fiber, complemented by a networkof collagen IV. These proteins are linked by entactin-1 (alsocalled nidogen-1) to form a complex structure containing ahigh number of binding sites, for example, for proteoglycansand integrins (Fig. 1). In skeletal muscle, the interstitial fi-broblasts are responsible for the production and excretion ofECM molecules. During development and regeneration,mononuclear muscle cells also synthesize and remodel ECM,whereas the contribution of the adult muscle cell is relativelysmall.80 Homing, residence, and activation of stem cells canbe regulated through differential expression of integrins andtissue-specific laminin isoforms in the BM.81–84 Integrity ofthe BM is crucial to keep the stem cells physically in place;defects or regulated gaps in the BM will allow cells to movethrough the tissue.85
Integrins are involved in linking the BM to the intracel-lular cytoskeleton86 and consist of a large family of cellsurface receptors composed of an a and a b subunit. They actas signal transducers after binding to the appropriate ligand,influencing cell migration, cell shape, and cell–cell interac-tions.80,82,87 Integrin a7 is the main isoform in mature skeletalmuscle.88,89 It binds muscle fibers to laminin and dystro-glycan and is upregulated during regeneration.90,91 Myo-blasts and newly formed myotubes in vitro express integrina5,88 and together with integrin b1 it forms the main receptorcomplex for fibronectin, which is also present in the BM.92,93
Integrin a3 is found on quiescent satellite cells and myo-blasts and plays a role in migration and differentiationby forming complexes with the integrin b1 subunit andA disintegrin and metalloproteinase 12 (ADAM12) (see endof this section).31,94 Integrin b1 plays a role in lamininbinding of myoblasts in vitro.89,93,95 While these integrins areof obvious importance for mechanical coupling and deficientmice develop different types of muscular dystrophy, a role inregeneration remains speculative.31,96,97
One of the BM components that is specific for muscle andtherefore is likely to play an important role in the nichefunctioning is laminin-2. Laminins are heterotrimers com-posed of a, b, and g subunits that form a network-likestructure in BMs (Fig. 1). Laminin-2 is composed of a2, b1,and g1 proteins and is also referred to as merosin.98 Thelaminin a2 subunit is the muscle-specific part of laminin-2and is connected to muscle fibers through integrin a7b1 anddystroglycan99 in a large dystrophin-associated proteincomplex.85,100,101 The significance of laminin a2 for satellitecell function is underscored by the phenotype of the laminina2 knockout mouse. Not only is the skeletal muscle BM al-most completely absent in these animals102 leading to a de-crease in the relative amount of satellite cells,103 duringregeneration the amount of myoblasts is additionally de-creased due to reduced proliferation rates103 and increasedapoptosis.102
Multiple proteoglycans can be found in the ECM in skel-etal muscle, but only a few seem to be important duringregeneration. Proteoglycans consist of glycosylated coreproteins with one or more covalently attached sulfated gly-cosaminoglycan chains. Quiescent satellite cells expresssyndecan-3 and -4, which are transmembrane HSPGs thatbecome upregulated upon activation. They only differ intheir extracellular domains104 and are required to transducesignals105 directly through binding to signaling molecules orby presenting them to their specific receptors.106 Syndecan-4has been implicated in fibroblast growth factor (FGF) sig-naling107,108 and seems to be required for early satellite cellactivation and proliferation. Satellite cells in knockout miceexpress reduced levels of syndecan-3 and c-met, and the BMappears disorganized in vivo. When muscle damage is in-duced in these animals, regeneration fails and results innonfunctional myofibers and scar tissue.109 In cell culture,proliferation of myoblasts is delayed and differentiation doesnot even take place.109 In syndecan-3�=� mice, the number ofsatellite cells and myonuclei is increased in muscles in spiteof normal size, location, and gene expression profile of sat-ellite cells and intact BM. When cells isolated from these miceare cultured, differentiation is abnormal, which is evident byaberrant fusion into syncytia instead of fibers.109 Therefore, itseems that integrity of the BM and the ability of cells to bindto the BM (for instance through HSPGs) is essential for re-generation.
In addition to laminins and HSPGs, growth factors play animportant role in the regeneration process. They can beproduced and secreted by muscle cells or immune cells andcan be liberated from the ECM where they are bound toproteoglycans.110 Growth factors that are involved in theregeneration program include hepatocyte growth factor(HGF), members of the transforming growth factor-b (TGF-b) superfamily, FGFs, and insulin-like growth factor-1 (IGF-1) isoforms. HGF is a heparan-binding protein that activatesquiescent satellite cells through its receptor c-met111–113 andis normally present in an active form in the ECM of unin-jured muscle.114 HGF is released by matrix metalloprotei-nases (MMPs)114,115 after stretch or other types of injury116
and can be produced by satellite cells in vitro.117 Next to HGF,FGFs are involved in the regulation of regeneration. FGFs 2,4, and 6 stimulate proliferation of myoblasts in vitro,118 butonly in the presence of HGF. FGF2 can be secreted by infil-trating macrophages119 and is found to be upregulated in
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regenerating muscle120 together with FGF6, which is thoughtto be secreted by injured muscle fibers.121,122 FGF6 knockoutmice show a severe regeneration defect that is most likelycaused by disturbed activation or proliferation of satellitecells.123 Migration of FGF6�=� myoblasts is also impaired.124
IGF-1 isoforms resemble FGFs in their actions. At leastfour different isoforms exist, two of which play a role inmuscle growth and repair.125 Mechano growth factor (MGF),which is induced during the initial satellite cell activation,126
especially after mechanical stimulation127 and damage,128
stimulates proliferation of myoblasts.129 After this initialphase, MGF is replaced by systemic IGF-1, through alterna-tive splicing.128,130 Systemic IGF-1 has been shown to inducefaster differentiation in C2C12 myoblasts131 and increasedregeneration in mice.132 In IGF-1 transgenic mice, myoblastproliferation and differentiation is augmented,133 whereasIGF-1 knockout mice die at birth because of severe muscu-lar dystrophy.134 In contrast to IGFs, several members ofthe TGF-b superfamily, including TGF-b, bone morphoge-netic proteins (BMPs), and myostatin, are involved in neg-ative regulation of regeneration by inhibiting proliferationor differentiation. TGF-b135,136 and myostatin137,138 reducemyoblast recruitment and differentiation, and TGF-b alsoremodels and repairs ECM and BM.139 In a number of knownstem cell niches (e.g., in neural crest140), BMPs prevent stemcell proliferation, which can be counteracted by upregulationof Noggin.141,142 In C2C12 myoblasts and satellite cells,BMP4 in combination with Notch signaling can block myo-genic differentiation.143
To get to the site of injury for repair, myoblasts have tomigrate through the ECM. MMPs are involved in degradingECM components, which not only enables myoblast migra-tion but also leads to release of and exposure to cytokinesand growth factors that target myoblast proliferation anddifferentiation.94,144–147 MMP2 and 9 can be secreted by sat-ellite cells148,149 and are upregulated in muscle during injuryand regeneration.150–152 They degrade not only collagen IVbut also other BM components such as dystroglycan,85 andare secreted into the ECM in an inactive form that is acti-vated after cleavage. Inhibition of these MMPs preventsmigration of myoblasts in vitro,148,153 and when injectedin vivo, migration of myoblasts is triggered.147 ADAMs arecell surface receptors involved in regeneration by mediatingadhesion and transmembrane signaling. ADAM12, also calledmeltrin-a, is expressed during muscle development and re-generation.31,154,155 It is also expressed in activated satellitecells156 and binds to integrin a7b1,93 integrin a9b1,157–159
integrin a3b1,31 and cell surface syndecans (probably syn-decan-4), leading to integrin-dependent spreading of cells.160
Obviously, the BM plays a crucial role in maintaining thestem cell function of satellite cells. However, it is hard toconsider the effects of integrins, different matrix proteins,growth factors, and MMPs individually because they all playinterconnected roles in the complex signaling pathways be-tween the satellite cell and its environment.
Mechanical Properties
It is clear, although under-appreciated, that the mechani-cal properties of the matrix greatly affect cellular phenotype.Examples are surface tension–induced cellular organizationduring embryonic development161 and locomotion.162 In
muscle cells (cyclic) stretch has been shown to induce hy-pertrophy163 and protein expression of myogenic regulatoryfactors164 and IGF-1 splice variants,127 activate satellitecells,116,165,166 and improve tissue-engineered muscle con-structs.60,167–169
Cells can feel their surroundings by anchoring and pullingwith their cytoskeletal proteins, integrins, and other mole-cules that mediate adhesion to the ECM.170 Recently, thestiffness of the substratum that cells are cultured on hasgained interest. Mesenchymal stem cells, for example, dif-ferentiate into the neuronal, muscular, or osteogenic lineagewhen cultured on substrates with a stiffness of 0.1–1 kPa, 8–17 kPa, and 25–40 kPa, respectively. After 1 week on such amatrix, differentiation pathways seem to be fixed and canno longer be reprogrammed with specialized media.171 Forskeletal muscle cell differentiation and especially maturationinto mature, striated skeletal muscle, the stiffness of the en-vironment is equally important172,173 (personal observations).
FIG. 3. Cross-striations in myotubes depend on substratestiffness. Two or 4 weeks after plating cells on collagen-coated polyacrylamide gels of different stiffnesses, onlymyotubes on gels of intermediate stiffness showed cross-striations of myosin. Bars: 20mm. Reproduced from TheJournal of Cell Biology, 2004, 166:877–887. ª 2004 The Rock-efeller University Press. Color images available online atwww.liebertonline.com=ten.
REGULATION OF SATELLITE CELLS BY STEM CELL NICHE 423
Muscle has been shown to possess a Young’s modulus ofabout 12 kPa in rest when measured in the transversedirection (the direction of adhesion of cells), which is thesame as for differentiating skeletal muscle cells in vitro.174
Differentiation and maturation of myoblasts have beenshown to be optimal on this stiffness. When C2C12 murinemyoblasts were cultured on gels with different Young’smoduli, cross-striation, which is an indicator of muscle mat-uration, only occurred on gels of intermediate stiffness (8 and11 kPa)173 (Fig. 3) or on top of a layer of myotubes (Young’smodulus, 12–15 kPa).173 Probably, the proliferative capacityof cells175 is also influenced by substrate stiffness (personalobservations), which could partly explain the discrepancybetween the in vivo and in vitro proliferative behavior of sat-ellite cells. Primary myoblasts were shown to proliferate at ahigher rate on stiffer gels (12 and 45 kPa) compared to softergels (1 kPa).175
This aspect deserves further exploration because it is likelyto be of importance not only for standardization of cell cultureexperiments but also for the design of matrices that supportcell therapies in regenerative medicine. In terms of mechanicalproperties, for example, the recipient environment in patientsthat qualify for MTT is very different from the required en-vironment for myoblast proliferation and differentiation. Inmdx mice and Duchenne patients, extensive scar formationreplaces the affected muscles, and this fibrotic tissue mightprevent myoblasts from surviving and regenerating the dis-eased muscle, not only by interfering positionally, but also byincreasing stiffness beyond the optimal parameters for myo-blast proliferation and differentiation.40
The BM and, most importantly, its collagen=laminin net-work are probably responsible for determining the stiffnessof muscle fibers.80,151,176 However, up till now, no mechani-cal tests have been performed on muscle BM. Nonetheless,not only the mechanical properties themselves but also thecombination of stimulatory effects with the different BMcomponents can have synergistic, complementary, or oppos-ing effects on myogenesis. For example, mechanical stimula-tion through the laminin receptor results in differentiationof C2C12 murine myoblasts and has been shown to be me-diated through b1 integrins, whereas mechanical stimulationthrough the fibronectin receptor encourages proliferation.164
In summary, the mechanical properties of the satellite cellniche are almost certainly determined by the BM and arepivotal for proper stem cell function of satellite cells. How-ever, it is not likely that the stiffness of the environment isactively regulated to trigger different processes in the re-generative process; it could therefore be considered to be anessential requirement.
Cells
Another important niche component is the cells other thanthe stem cells. For bone marrow for instance, these supportingcells, most notably osteoblasts, play an important role in stemcell maintenance and regulation (reviewed by Wilson andTrumpp4). In the muscle stem cell niche, mature muscle cells,other mesenchymal cells, and cells of the specific and innateimmune system connect with the satellite cells.
In the normal situation, satellite cells are only in directcontact with the adjacent muscle cell. The importance of thisconnection is underscored by the fact that the result of
myoblast transplantation is better when fibers containingsatellite cells are transplanted as a whole compared totransplantation of cells liberated from the fiber by enzy-matic digestion.15 However, when satellite cells are dissoci-ated from the muscle fiber by physical trituration, theirregenerative potential in vivo is comparable to transplan-tation of single fibers. Therefore, although the parent fi-ber itself does not seem to be required for satellite cellfunction, the ability of the satellite cell to bind and commu-nicate to the fibers or the niche present in the recipientmuscle seems to be essential and might be impaired by en-zymatic digestion.15
In the event of injury and muscle damage, cells of theimmune system are also able to come into contact with thesatellite cell and convey signals directing proliferation, mi-gration, and differentiation, for example, through the pro-duction and excretion of growth factors. Macrophages areimportant for removal of dead cells and the dead parts ofmuscle fibers. They have also been shown to be able to di-rectly stimulate satellite cell proliferation and delay theirdifferentiation. This effect is probably mediated by FGF2,platelet derived growth factor (PDGF), or leukemia in-hibitory factor (LIF).
More than 60% of the satellite cells are located close tocapillaries and are thought to receive signals from endothe-lial cells although they are not in direct contact with them.The number of capillaries per muscle fiber has been shown tocorrelate to the number of satellite cells, and loss of capil-laries leads to loss of satellite cells, pointing to some sort ofinteraction.70 In addition, transwell experiments showed thatendothelial cells have a positive effect on proliferation ofmyoblasts, which is mediated by growth factors.70
Cell–cell interactions have been shown to be pivotal formuscle regeneration and can be mediated by components ofthe cell-bound receptor–ligand complexes of the Notch andWnt family. Wnt signaling plays a role in stem cell deter-mination177 in different stem cell niches (e.g., the intestinalstem cell niche142) and is also thought to activate stem cellsduring muscle regeneration.8,178 The canonical Wnt pathwayis mediated by b-catenin, which translocates to the nucleuswhere it induces transcription of specific genes involved incell proliferation and survival together with transcriptionfactors of the Tcf=Lef family. Overexpression of b-cateninincreases proliferation and induces hypertrophy in vitro inC2C12 myoblasts and increases regeneration and the numberof satellite cells in vivo in mice.179
Notch is an evolutionary conserved heterodimeric trans-membrane receptor that is involved in cell fate control bylocal cell interactions. Most of the ligands involved in Notchsignaling are also membrane bound and interact with Notchreceptors on adjacent cells, leading to a signaling cascadethat regulates the transcription of specific genes involved inself-renewal, proliferation, and differentiation of stem cellstogether with functional Wnt signaling.180–183 During muscleregeneration, satellite cells are activated and start prolifer-ating due to Notch signaling, through the ligand Delta-1.32,76,184–186
Different types of coculture experiments have been per-formed to investigate the effect of contact with a muscleenvironment on different types of cells. In general, it seemsto be the case that direct contact with either muscle fibers ormyoblasts is essential for myogenic conversion.187–191
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Overall, the ability to bind to and be in direct contactwith muscle fibers seems to be essential for the regenera-tive potential of satellite cells. Different cell–cell interac-tion and signaling molecules seem to play an important rolein this process, although we need more direct results toexplain some of the contradictory roles attributed to thesemolecules.
Discussion
Satellite cells from skeletal muscle are identified as corre-late of a tissue-resident stem cell; that is, they are capable ofin vivo tissue regeneration.10,12,15,18,22 Since satellite cells areeasily identifiable and can be harvested from intact muscle,therapeutic applications for MTT or for tissue engineeringhave been envisaged. However, it appears that the myoblastpopulation that is harvested from adult skeletal musclequickly loses its self-renewal capacity during in vitro ex-pansion.27,192,193
Pivotal evidence suggests that the isolation procedureand=or in vitro expansion causes this fate change; enzymat-ically isolated or cultured myoblasts have been shown to losetheir regenerative capacity, whereas direct implantation ofnonenzymatically isolated myoblasts or single fibers withresident satellite cells is extremely effective to regeneratedamaged muscle tissue.15 In addition, when sliced musclegrafts are used in muscle transplantation, cells survive for upto a year.194–196
We suggest that preservation of critical stem cell nichecomponents is important for maintaining the regenera-tive capacity of satellite cells. We have reviewed the BMcontribution to this niche. Appealing candidates are muscle-specific laminin isoforms81 and syndecans 3 and 4.109 How-ever, systematic studies addressing the essential componentsfor the satellite stem cell niche are needed. Once identified,reconstitution of these components during cell culture mightimprove the applicability of satellite cells in regenerativemedicine. An under-appreciated aspect of the stem cell nicheis the mechanical framework it provides. There is now in-creasing evidence that cells sense the mechanical propertiesof their matrix and respond by phenotypic change,171,173
possibly by differentiating away from their precursor state(e.g., in the case of rigid culture plastic). Support for theimportance of the matrix in the stem cell niche also comesfrom observations that BM integrity during injury acceleratesnatural healing.84,197 Not only loss of the matrix context butalso loss of the cellular context may cause fate change of thesatellite cell. Experience with cocultures of cells of differentorigins with adult muscle fibers or myoblasts strongly sug-gests that physical contact of stem cells with differentiatedmuscle favors muscular differentiation.187–191
In addition, the isolation procedure might select non-regenerative subpopulations of satellite cells.79 Differentsubpopulations of stem cells in skeletal muscle appear toexist, and it is very likely that some have more regenerativecapacity than others.15,19,38 Clearly, detailed marker studiescomplemented by clonal analyses are required to dissect theimportance of these subpopulations and the extent to whichthe isolation procedure affects their presence and perfor-mance.
Elucidating the microenvironmental needs of satellite cellswill have considerable implications for the use of these cells
for regenerative medicine. In addition, the two approaches,MTT and tissue engineering, will likely differ in their re-quirements concerning proliferative and migratory capacity.The indications and therefore the recipient characteristics, forinstance large defects in tissue engineering versus general-ized dystrophy for MTT, will be different as well.
For both therapies to advance it is therefore essential thatwe understand the biochemical, cellular, and mechanicalcues that promote satellite cell proliferation and differentia-tion in vitro and in vivo. The current evidence provides asound basis for systematic studies of these cues in the settingof regeneration of skeletal muscle.
Disclosure Statement
No competing financial interests exist.
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Address reprint requests to:Kristel J.M. Boonen, M.Sc.
Department of Biomedical EngineeringEindhoven University of Technology
WH 4.12, P.O. Box 5135600 MB Eindhoven
The Netherlands
E-mail: [email protected]
Mark J. Post, M.D., Ph.D.Department of Physiology
Maastricht UniversityUns 50 3.154, P.O. Box 616
6200 MD MaastrichtThe Netherlands
E-mail: [email protected]
Received: January 22, 2008Accepted: August 4, 2008
REGULATION OF SATELLITE CELLS BY STEM CELL NICHE 431
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