The Skeletal Muscle Satellite Cell Journal of Histochemistry

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  The Skeletal Muscle Satellite Cell: The Stem Cell That Came in From the Cold
             Peter S. Zammit, Terence A. Partridge and Zipora Yablonka-Reuveni
                          J Histochem Cytochem 2006 54: 1177
                               DOI: 10.1369/jhc.6R6995.2006

                        The online version of this article can be found at:
                          http://jhc.sagepub.com/content/54/11/1177


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                                                                                                                                                                           Volume 54(11): 1177–1191, 2006
                                                                                                                                                                Journal of Histochemistry & Cytochemistry
                                                                                                                                                                                 http://www.jhc.org


                                                REVIEW


                                                The Skeletal Muscle Satellite Cell: The Stem Cell That Came in
                                                From the Cold

                                                Peter S. Zammit, Terence A. Partridge, and Zipora Yablonka-Reuveni
                                                Randall Division of Cell and Molecular Biophysics, King’s College London, London, England (PSZ); Children’s National Medical
                                                Center, Washington, DC (TAP); and Department of Biological Structure and Institute for Stem Cell and Regenerative
                                                Medicine, University of Washington School of Medicine, University of Washington, Seattle, Washington (ZY-R)
The Journal of Histochemistry & Cytochemistry




                                                SUMMARY         The muscle satellite cell was first described and actually named on the basis of
                                                its anatomic location under the basement membrane surrounding each myofiber. For many
                                                years following its discovery, electron microscopy provided the only definitive method of
                                                identification. More recently, several molecular markers have been described that can be
                                                used to detect satellite cells, making them more accessible for study at the light microscope
                                                level. Satellite cells supply myonuclei to growing myofibers before becoming mitotically
                                                quiescent in muscle as it matures. They are then activated from this quiescent state to fulfill
                                                their roles in routine maintenance, hypertrophy, and repair of adult muscle. Because muscle is
                                                able to efficiently regenerate after repeated bouts of damage, systems must be in place to                                  KEY WORDS
                                                maintain a viable satellite cell pool, and it was proposed over 30 years ago that self-renewal                              satellite cell
                                                was the primary mechanism. Self-renewal entails either a stochastic event or an asymmetrical                                stem cell
                                                cell division, where one daughter cell is committed to differentiation whereas the second                                   myogenesis
                                                continues to proliferate or becomes quiescent. This classic model of satellite cell self-renewal                            myoblast
                                                and the importance of satellite cells in muscle maintenance and repair have been challenged                                 skeletal muscle
                                                during the past few years as bone marrow-derived cells and various intramuscular pop-                                       Pax7
                                                ulations were shown to be able to contribute myonuclei and occupy the satellite cell niche.                                 self-renewal
                                                This is a fast-moving and dynamic field, however, and in this review we discuss the evidence                                regeneration
                                                that we think puts this enigmatic cell firmly back at the center of adult myogenesis.                                       MyoD
                                                                                                                   (J Histochem Cytochem 54:1177–1191, 2006)                aging




                                                THE IDEA OF WRITING THIS REVIEW arose after the mini-                            erative myogenesis. To some of us, one it never really
                                                symposium ‘‘Adult Stem Cells: Origin and Differenti-                             lost! That it was time to finally finish this review was
                                                ation’’, which was held during the 6th Joint Meeting                             realized during the recent MRC Clinical Sciences
                                                of the Histochemical Society and the Japan Society of                            Centre symposium ‘‘From Satellite Cells to Gene Ther-
                                                Histochemistry and Cytochemistry in July 2002 in                                 apy’’ that took place in September 2005 in London,
                                                Seattle, Washington. At that time, the importance of the                         where the satellite cell again seemed to be preeminent
                                                satellite cell in adult myogenesis was being questioned,                         among muscle stem cells.
                                                with cells derived from bone marrow and vasculature,                                This review has undergone many revisions, the result
                                                among others, being ascribed a central role in regen-                            of working in such a dynamic and exciting field with so
                                                erative myogenesis. During the following years, the                              many talented colleagues. We have not tried to provide
                                                satellite cell regained its place at the center of regen-                        a comprehensive literature survey but rather to just
                                                                                                                                 discuss topics relevant to the role of this enigmatic cell.

                                                   Correspondence to: Dr. Peter Zammit, Randall Division of Cell
                                                and Molecular Biophysics, King’s College London, New Hunt’s                      Historical Perspective
                                                House, Guy’s Campus, London, SE1 1UL England. E-mail: peter.                     The year 1961 was momentous for skeletal muscle,
                                                zammit@kcl.ac.uk. Co-corresponding author: Dr. Zipora Yablonka-                  being marked by publications that established the
                                                Reuveni. E-mail: reuveni@u.washington.edu
                                                   Received for publication April 19, 2006; accepted July 27, 2006               dominant model of the cell biology of skeletal muscle
                                                [DOI: 10.1369/jhc.6R6995.2006].                                                  for the remainder of the 20th century. The first was the

                                                C The Histochemical Society, Inc.               0022-1554/06/$3.30                                                                                 1177

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                                                1178                                                                                                        Zammit, Partridge, Yablonka-Reuveni

                                                demonstration that the multinucleated skeletal myofi-                         definition of a stem cell, in that it can give rise to a dif-
                                                ber, the contractile unit of muscle, is formed by the                         ferentiated cell type and maintain itself by self-renewal.
                                                fusion of large numbers of mononucleate myoblasts
                                                (Cooper and Konigsberg 1961; Stockdale and Holtzer
                                                1961). This effectively resolved the problem first noted                      What Is the Developmental Origin of
                                                by Lewis and Lewis (1917) that myofibers seemed to                            Satellite Cells?
                                                increase in size and in content of nuclei in the absence of                   The prevailing hypothesis is that satellite cells in mam-
                                                any observable nuclear division within the myofiber.                          mals and birds are derived from somites (Armand et al.
                                                The complementary discovery consisted of electron mi-                         1983), transitory mesoderm-derived structures formed
                                                croscopic descriptions of an apparently quiescent cell                        in pairs on either side of the neural tube. Somites then
                                                lying on the surface of the myofiber, but beneath its                         differentiate into dermomyotome and sclerotome, and
                                                basement membrane, where its peripheral position                              mesodermal cells become specified as skeletal muscle
                                                earned it the name Fsatellite_ cell (Katz 1961; Mauro                         precursors within the nascent myotome (Christ et al.
                                                1961). Although first described in anuran amphibians,                         1975; Braun et al. 1992; Rudnicki et al. 1993). Myo-
The Journal of Histochemistry & Cytochemistry




                                                the satellite cell occupies an identical anatomical posi-                     genic precursors continue to be generated within the
                                                tion in the majority of vertebrates and acquired imme-                        somite (Ben-Yair et al. 2003) and eventually give rise to
                                                diate and almost unquestioned candidacy as the source                         epaxial muscles (deep back muscles), whereas others
                                                of myogenic cells for growth and repair of postnatal                          migrate from the myotomal lips to populate the muscles
                                                skeletal muscle.                                                              of the limb and diaphragm fields.
                                                   In general, stem/progenitor cells have been identified                        Myoblasts isolated from different developmental
                                                and characterized in terms of molecular markers, which                        stages have distinct characteristics (e.g., Bonner and
                                                have then been used to trace them to their anatomical                         Hauschka 1974) and can be distinguished from those
                                                niche within a tissue. In the case of the satellite cell,                     isolated from peri- and postnatal muscle (reviewed in
                                                attribution of a stem cell-like status to an anatomically                     Cossu and Molinaro 1987 and Yablonka-Reuveni 1995).
                                                defined entity made it difficult to devise stringent tests                    Satellite cells can first be identified morphologically
                                                because its role in regeneration usually moves it out of                      by their appearance underneath the forming basement
                                                its position immediately beneath the basal lamina.                            membrane toward the end of the fetal period (Ontell
                                                Thus, the principal defining characteristics of a satellite                   and Kozeka 1984). Concurrence of the time when adult-
                                                cell are removed, destroying any formal connection                            type myoblasts can first be identified in later stages of
                                                between it and the myoblasts that eventually differen-                        embryogenesis and the time when satellite cells can
                                                tiate into newly formed muscle. Evidence that satellite                       be identified morphologically in situ has supported the
                                                cells function as myogenic precursors was initially                           notion that satellite cells represent a unique subset of
                                                based on studies of the distribution of labeled thymi-                        myogenic progenitors (Hartley et al. 1991; Feldman
                                                dine in growing or regenerating muscles (reviewed in                          et al. 1993). This may be further reflected by the vary-
                                                Grounds and Yablonka-Reuveni 1993), which collec-                             ing roles of the myogenic regulatory factors (MRFs), a
                                                tively led to the commonly accepted view that satellite                       family of muscle-specific helix–loop–helix transcription
                                                cells divide to provide myonuclei to growing myofibers                        factors comprising Myf5, MyoD, Mrf4, and myogenin.
                                                (Moss and Leblond 1971) before becoming mitotically                           Mrf4 acts only as a myogenic determination factor in em-
                                                quiescent in normal mature muscle (Schultz et al. 1978).                      bryonic cells (Kassar-Duchossoy et al. 2004), whereas
                                                Conclusive proof that satellite cells directly give rise to                   myogenin is required only for differentiation before
                                                myoblasts was shown only with isolated myofibers,                             birth (Knapp et al. 2006). Furthermore, the seminal ob-
                                                a technique pioneered by Bischoff (1975,1986) and                             servation that embryonic and fetal myogenesis is largely
                                                Konigsberg et al. (1975), among others (Yablonka-                             unperturbed in mice lacking the paired box transcrip-
                                                Reuveni and Rivera 1994; Rosenblatt et al. 1995;                              tion factor Pax7, although postnatal growth is severely
                                                Beauchamp et al. 2000). In these studies, viable myo-                         affected, points to a unique requirement of satellite cells
                                                fibers were isolated from the muscle by enzymatic di-                         for this transcription factor (Seale et al. 2000). Proposed
                                                gestion, complete with their cohort of satellite cells still                  myogenic stem cells within the mouse somite express
                                                resident beneath the basal lamina. When cultured, the                         Pax3 and Pax7 but no myogenic-specific markers. It
                                                satellite cells proliferated, giving rise to satellite cell-                  has been suggested that this same cell population later
                                                derived myoblasts that differentiated to produce multi-                       generates satellite cells, certainly during the postna-
                                                nucleated myotubes. Recently, transplantation of such                         tal period (Kassar-Duchossoy et al. 2005; Relaix et al.
                                                single myofibers into muscle has provided good evi-                           2005) with similar observations made in chicken (Gros
                                                dence that the satellite cell indeed acts as a myogenic                       et al. 2005). These studies were restricted to examining
                                                stem cell in vivo, able to give rise to both new myofibers                    late fetal and/or early postnatal stages for the presence
                                                and, importantly, also many new satellite cells (Collins                      of marked satellite cells. Therefore, cells identified with
                                                et al. 2005). The satellite cell therefore fulfills the basic                 genetic markers at late fetal or early postnatal period



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                                                The Satellite Cell: The Preeminent Muscle Stem Cell                                                                               1179

                                                may simply be required for postnatal growth and never                       tive means of identifying the total population of satellite
                                                actually become quiescent satellite cells in adult. The                     cells on isolated myofibers (Beauchamp et al. 2000). In
                                                elegant work of Schienda et al. (2006) extends the ex-                      normal mature muscle, satellite cells are mitotically
                                                amination period to 4–6 weeks and shows that many                           quiescent (Schultz et al. 1978) and express Pax7 (Seale
                                                satellite cells in adult muscle are derived from the hyp-                   et al. 2000), the adhesion molecule M-cadherin (Irintchev
                                                axial somites, augmenting earlier studies.                                  et al. 1994), and saliomucin CD34 (Beauchamp et al.
                                                    Not all satellite cells are of somitic origin. Some head                2000), among others (reviewed in Charge and Rudnicki
                                                muscles are unique in that they do not derive from                          2004) (Figure 1 and Figure 2). In addition, the Myf5
                                                somites but rather from prechordal mesoderm and have                        locus is clearly active in quiescent satellite cells as shown
                                                a distinct genetic network controlling their formation                      using the Myf5nlacZ/1 mouse (Tajbakhsh et al. 1997;
                                                (Tajbakhsh et al. 1997; Lu et al. 2002; Tzahor et al.                       Beauchamp et al. 2000; Shefer et al. 2006) and several
                                                2003). Interestingly, mutant mice lacking Pax3 or c-Met                     transgenic mouse lines (Zammit et al. 2004a), but
                                                (the hepatocyte growth factor receptor) do not have                         whereas wild-type Myf5 mRNA can be detected in qui-
                                                cells that migrate from somites to populate the limb and                    escent satellite cells (Day K and Yablonka-Reuveni Z,
The Journal of Histochemistry & Cytochemistry




                                                give rise to muscle. Rare myogenic cells, however, are                      unpublished data) there is, as yet, no definitive evidence
                                                still found in the limbs of embryos of these knockout                       that the protein itself is present. The Myf5nlacZ/1mouse
                                                mice, which share markers in common with hemato-                            also provides a useful marker for the contribution of
                                                poetic and endothelial cells such as CD34 and flk                           donor cells to the satellite cell pool following trans-
                                                (De Angelis et al. 1999), and CD34 is certainly ex-                         plantation (Heslop et al. 2001; Collins et al. 2005).
                                                pressed by adult satellite cells (Beauchamp et al. 2000).                   Recent markers that can be added to the list of those
                                                Furthermore, endothelial cells in skeletal muscle micro-                    used to identify quiescent satellite cells include lysenin,
                                                vasculature contain Sca1 (Zammit and Beauchamp                              which reports sphingomyelin levels in the cell mem-
                                                2001), and rare satellite cells express eGFP in a Sca1                      brane (Nagata et al. 2006) and caveolin 1 (Volonte
                                                transgenic mouse (Mitchell et al. 2005). This raises the                    et al. 2005).
                                                possibility of a common origin for endothelial cells and                        Pax7 is probably the most useful current marker for
                                                some satellite cells (Kardon et al. 2002), or that endo-                    identifying quiescent satellite cells due to the availabil-
                                                thelial cells may be able to give rise to satellite cells.                  ity of a good antibody (Seale et al. 2000; Halevy et al.
                                                Intriguingly, mesangioblast cell lines derived from fetal                   2004; Zammit et al. 2004b; Shefer et al. 2006) (Figure 1
                                                vessels (Minasi et al. 2002; Sampaolesi et al. 2003) or                     and Figure 2). It should be noted that markers such as
                                                cells from neonatal bone marrow and fetal liver                             CD34 are not specific to satellite cells but are useful
                                                (Fukada et al. 2002) are able to generate cells that                        markers on isolated myofibers because distinguishing
                                                can occupy the satellite cell niche following transplan-                    satellite cells from other positive cells (e.g., endothelial
                                                tation into adult muscle. Whether these tissues are                         cells) on muscle sections is more difficult. Such analysis
                                                normal sources of satellite cells during development,                       often requires not only the satellite cell marker but also
                                                however, remains speculative at best. Indeed, rare myo-                     coimmunostaining to identify the basal lamina (see
                                                genic cells can be found in a number of organs not                          Figure 2).
                                                sharing a common embryological origin including the                             To fulfill their role in muscle maintenance, hyper-
                                                brain, lungs, kidneys, and intestines during chicken                        trophy, and repair, satellite cells must first be activated
                                                fetal development (Gerhart et al. 2001), which may                          from this quiescent state to produce myoblast progeny
                                                simply reflect aberrant migration or differentiation of                     (reviewed in Charge and Rudnicki 2004 and Wozniak
                                                pluripotent cells.                                                          et al. 2005). Satellite cell-derived myoblasts are gener-
                                                                                                                            ally characterized by the same set of myogenic markers
                                                                                                                            as myoblasts derived from almost any developmental
                                                Molecular Markers of Satellite Cells                                        stage (Figure 3). When satellite cells are activated, they
                                                The anatomic definition of a satellite cell meant that                      rapidly initiate MyoD expression (Fuchtbauer and
                                                their characterization initially relied on ultramicroscopic                 Westphal 1992; Grounds et al. 1992; Yablonka-
                                                criteria and so, by definition, all cells located beneath                   Reuveni and Rivera 1994) (Figure 2E) and undergo a
                                                the basal lamina of a myofiber are satellite cells, regard-                 CD34 isoform switch, continuing to coexpress Pax7,
                                                less of their function or gene expression profile. The                      M-cadherin, and Myf5. They then begin to divide, ex-
                                                relatively recent advent of molecular markers has al-                       pressing additional genes typical of cycling cells such
                                                lowed the reliable identification of satellite cells at the                 as PCNA. Myogenin then marks the onset of myo-
                                                light microscope level (Figure 1 and Figure 2). The                         genic differentiation (Fuchtbauer and Westphal 1992;
                                                3F-nlacZ-E transgene (Kelly et al. 1995) marks all myo-                     Grounds et al. 1992; Yablonka-Reuveni and Rivera
                                                nuclei in fast myofibers with b-galactosidase; there-                       1994; Yablonka-Reuveni et al. 1999b; Zammit et al.
                                                fore, detecting nuclei lacking reporter gene activity                       2004b) together with a variety of regulatory and struc-
                                                with 4,6-diamidino-2-phenylindole provides an effec-                        tural muscle genes typical of skeletal muscle myocytes.



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                                                1180                                                                                                               Zammit, Partridge, Yablonka-Reuveni
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                                                Figure 1 Distribution of muscle satellite cells on isolated myofibers. Myofibers were isolated from the extensor digitorum longus (EDL), soleus,
                                                and tibialis anterior (TA) of an adult mouse and immunostained for M-cadherin to locate satellite cells (A). Satellite cells appear distributed
                                                randomly along the entire length of TA and EDL myofibers, but soleus myofibers usually have an accumulation of satellite cells around the
                                                motor end plate where the motoneuron contacts the myofiber (arrow in A). An isolated soleus myofiber, coimmunostained with Pax7 (green,
                                                B) to identity satellite cells (arrows in B,C) and a-bungarotoxin (red, B) to locate the neuromuscular junction (arrowhead in B) clearly shows this
                                                accumulation of satellite cells around the motor end plate. All nuclei present were identified using 4,6-diamidino-2-phenylindole (DAPI)
                                                counterstaining (C). Bar: A 5 200 mm; B,C 5 14 mm. (A) Kindly provided by J. David Rosenblatt.




                                                The pattern of Mrf4 expression during satellite cell                                 young mice (Beauchamp et al. 2000). This could simply
                                                myogenesis is less clear because it can be expressed                                 be due to dynamic expression of some of the antigens
                                                either after, or prior to, initiation of myogenin ex-                                expressed by satellite cells in vivo and could be related,
                                                pression (Smith et al. 1993,1994). A schematic of the                                for example, to the length of time that the cells have
                                                dynamics of satellite cell markers as they transit from                              been quiescent. That the satellite cell pool may be
                                                quiescence to differentiation is shown in Figure 3.                                  composed of a heterogeneous population is certainly
                                                                                                                                     suggested by various functional observations. During
                                                Are Satellite Cells a Heterogeneous Population?                                      postnatal growth, cells in the satellite cell position in
                                                The use of molecular markers has indicated that there                                muscle can be separated into two typified categories
                                                may be heterogeneity within the satellite cell pool of                               according to their rate of cell division (Schultz 1996),



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                                                The Satellite Cell: The Preeminent Muscle Stem Cell                                                                                       1181
The Journal of Histochemistry & Cytochemistry




                                                Figure 2 Identification of muscle satellite cells using molecular markers. There is an ever-increasing number of molecular markers for
                                                identifying quiescent satellite cells, but Pax7 is probably the most useful at present. An isolated EDL myofiber coimmunostained for Pax7
                                                (green, A) and CD34 (red, B) shows a quiescent satellite cell on the surface of a myofiber (arrow in A–C). The 3F-nlacZ-E transgene marks all
                                                myonuclei in fast muscles and so provides an easy method to identify the whole satellite cell population on a myofiber, independently of
                                                antigen expression (Beauchamp et al. 2000). The Myf5nlacZ/1 mouse expresses the Myf5/b-gal fusion protein in quiescent satellite cells and so
                                                makes their recognition straightforward (Beauchamp et al. 2000). Detection of myonuclei using X-gal from the 3F-nlacZ-E transgene (blue, D)
                                                and a satellite cell using salmon-gal from the Myf5 targeted locus (arrow in D) on an isolated EDL myofiber from a double Myf5nlacZ//3F-nlacZ-E
                                                mouse (D). When satellite cells are activated (arrow in E), they rapidly coexpress MyoD (green, E) with CD34 (red, E). Pax7 can also be used
                                                to identify satellite cells on muscle sections, although this can be problematic on mouse tissue. Satellite cells (arrows in F,G) in a 49-day-old
                                                chicken pectoralis muscle section immunostained for Pax7 (green, F) with laminin (red, F) used to mark the basal laminae of muscle fibers. All
                                                nuclei present were identified by counterstaining with DAPI (blue, G). (F,G) Kindly provided by Benjamin Rosser and Mohammed Allouh; for
                                                further details see Halevy et al. 2004.


                                                although myogenic lineage markers were not used to                                  proliferation, whereas most myoblasts do not even
                                                confirm their identity. After muscle damage in adult,                               divide much before 24 hr (Rantanen et al. 1995).
                                                some myoblasts express myogenin within 8 hr and so                                  Differences between myogenic progenitors are also seen
                                                presumably commit to differentiation with little or no                              in culture where cells exhibit heterogeneity in prolifer-



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                                                1182                                                                                                              Zammit, Partridge, Yablonka-Reuveni
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                                                Figure 3 Schematic of satellite cell myogenesis and markers typical of each stage. Satellite cells are quiescent in normal adult muscle and can
                                                be activated by, for example, muscle damage. Once activated, satellite cells divide to produce satellite cell-derived myoblasts that further
                                                proliferate, before committing to differentiation and fusing to form myotubes, which then mature into myofibers (for clarity, satellite cell self-
                                                renewal is not included). CD34, Pax7, and Myf5/b-gal are expressed in quiescent satellite cells. Satellite cell activation is marked by the rapid
                                                onset of MyoD expression, whereas myogenin later marks the commitment to differentiation. The temporal expression pattern of MLC3F-tg is
                                                typical of many structural muscle genes such as skeletal muscle actin and MyHC, which mark sarcomeric assembly in the later stages of
                                                differentiation. Myf5/b-gal denotes the fusion protein product of the targeted allele of the Myf5nlacZ/1 mouse (Tajbakhsh et al. 1997), whereas
                                                MLC3F-tg is the product of the 3F-nlacZ-E transgene (Kelly et al. 1995). (Adapted from Miller et al. 1999 with modifications by J. Beauchamp
                                                and the authors.)




                                                ation rate and clonogenic capacity (Molnar et al. 1996).                            limb muscle is observed only following transplantation
                                                Finally, irradiation prevents muscle growth and main-                               of jaw muscle-derived myogenic precursors (Hoh et al.
                                                tenance due to the ablation of (most) satellite cells                               1988; Hoh and Hughes 1991). Similarly, the MyHC
                                                (Wakeford et al. 1991; LaBarge and Blau 2002), but a                                isoform that rodent satellite cell-derived myotubes
                                                subpopulation of myogenic precursor cells survive and                               express is correlated to the phenotype of the myofiber
                                                can still be recruited to regenerate muscle following a                             from which they originate (Dusterhoft and Pette 1993;
                                                substantial injury (Heslop et al. 2000). At present there                           Rosenblatt et al. 1996; Kalhovde et al. 2005). This does
                                                is no direct evidence linking behavioral and phenotypic                             not appear to be the case in man (Bonavaud et al.
                                                heterogeneity, and it may simply reflect the state of a                             2001), but it is possible that the phenomenon is seen
                                                satellite cell in a dynamic system.                                                 only when culturing myogenic cells on specialized ma-
                                                    The presence of different muscle fiber types classified                         trixes that permit long-term cultures such as Matrigel
                                                by the myosin heavy chain (MyHC) isoform they                                       (Hartley and Yablonka-Reuveni 1990). This predispo-
                                                contain provides a marker of muscle fiber heterogeneity                             sition of different satellite cell populations toward ex-
                                                that appears to be reflected in some populations of                                 pression of specific MyHC isoforms is manifested only
                                                satellite cells. For example, the presence of a cat jaw                             after differentiation, and no marker exists to distinguish
                                                muscle-specific superfast MyHC isoform in regenerated                               them beforehand.



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                                                The Satellite Cell: The Preeminent Muscle Stem Cell                                                                                 1183

                                                    Heterogeneity of satellite cells between different                        fates represent trans-differentiation or amplification of
                                                muscles is clearer. With head muscle, for example, the                        distinct subpopulations within the satellite cell niche.
                                                masseter regenerates poorly compared with limb mus-                           The observations of Hashimoto et al. (2004) that sin-
                                                cle (Pavlath et al. 1998), but the extent to which this is                    gle satellite cells can give rise to anatomically different
                                                dictated by the environment of masseter tissue has not                        progenitor types cells—myogenic ‘‘round cells’’ and
                                                been fully evaluated. This is reflected, however, in poor                     ‘‘thick cells’’ that can give rise to myogenic and oste-
                                                proliferation and differentiation of masseter-derived                         ogenic cells—seems to support the notion of separate
                                                myogenic cells in culture. Satellite cells in the extraoc-                    subpopulations within satellite cells. Moreover, in
                                                ular muscles remain proliferative and add myonuclei to                        salamander, satellite cells (Pax71ve) appear to contrib-
                                                the uninjured myofiber when their limb counterparts                           ute multipotential cells both in culture and during limb
                                                are quiescent (McLoon et al. 2004), and these muscles                         regeneration in vivo (Morrison et al. 2006). Whether
                                                are spared in Duchenne muscular dystrophy (Porter                             mammalian satellite cells are also able to show alter-
                                                et al. 2003). These phenomena may be related to spe-                          native differentiation programs in vivo is unknown, but
                                                cific environmental cues, but the myogenic progenitors                        the ectopic muscle ossification that occurs in fibrodys-
The Journal of Histochemistry & Cytochemistry




                                                themselves may also be different, reflecting their dif-                       plasia ossificans progressiva is thought to be the result
                                                ferent ontogeny from body muscles. Heterogeneity                              of overexpression of BMP4 (Shafritz et al. 1996), which
                                                exists, however, even among somite-derived muscles.                           may act on satellite cells in a similar manner to BMP2 in
                                                Mutant mouse lines in which the Pax3 locus has been                           culture. It is attractive to speculate that satellite-like
                                                targeted with eGFP provide the best current evidence of                       cells unable to turn on the MyoD gene may retain a
                                                heterogeneity between muscles where, for example,                             greater capacity to enter other mesenchymal lineages
                                                only the gracilus in the hindlimb contains significant                        (discussed in Shefer et al. 2004). In support of this
                                                numbers of eGFP (Pax3)-expressing satellite cells. In                         notion is the finding that myofibroblasts can express
                                                the upper body, many muscles contain large numbers of                         MyoD but are unable to fully execute the skeletal mus-
                                                satellite cells expressing eGFP (Pax3), the vast majority                     cle differentiation program (Walker et al. 2001). Simi-
                                                of which also express Pax7 (Relaix et al. 2006). There                        larly, human rhabdomyosarcoma cells also express
                                                does not seem to be any obvious reason why in the                             MyoD but do not differentiate into skeletal muscle
                                                Pax3eGFP/1 mouse certain muscles contain eGFP1ve                              because the factor is unable to activate transcription
                                                satellite cells, whereas neighboring ones do not. It does                     (Tapscott et al. 1993). Restoration of MyoD transcrip-
                                                not appear related to the ontogeny of the muscle or to                        tional activity, or the introduction of active Mrf4, pro-
                                                the muscle fiber type composition; therefore, the reason                      motes differentiation into skeletal muscle cells (Tapscott
                                                for this subpopulation remains a mystery. Although                            et al. 1993; Sirri et al. 2003).
                                                there is controversy as to whether this targeted allele
                                                faithfully reflects the expression of endogenous Pax3 in
                                                adult tissue (Horst et al. 2006), it certainly demon-                         Satellite Cells Remain Viable Throughout Life
                                                strates heterogeneity among satellite cells. When trans-                      The early experiments of Studitsky (1964) where mus-
                                                planted, cells from Pax3eGFP/1 mice maintain eGFP                             cles that were removed, minced, and replaced were still
                                                expression in a host muscle environment that does not                         able to form a new functional muscle really demon-
                                                normally contain such cells, indicating that this is                          strate the remarkable ability of this tissue to regenerate.
                                                probably lineage based (Montarras et al. 2005).                               Effective regenerative ability is still retained after re-
                                                    Whether this satellite cell heterogeneity is linked to                    peated cycles (up to 50) of extensive injury using myo-
                                                multipotency is also unknown. Until recently it was                           toxins (Sadeh et al. 1985; Luz et al. 2002). Even in the
                                                considered that satellite cells were unipotent and that                       absence of such overt damage, estimates of myonuclear
                                                their function was restricted to supplying myoblasts for                      turnover in rodents of 1–2% per week (Schmalbruch
                                                muscle maintenance and repair. Although cells isolated                        and Lewis 2000) combined with observations that most
                                                from muscle tissue are able to differentiate into both                        satellite cells only undergo one or two divisions in vivo
                                                myogenic and neurogenic lineages (Alessandri et al.                           before differentiation (Grounds and McGeachie 1987)
                                                2004) or adopt myogenic and endothelial fates (Tamaki                         mean that the pool of satellite cells would soon be ex-
                                                et al. 2002), the relationship of these cells to satellite                    hausted in adult muscle without replenishment.
                                                cells remains to be established. It has recently been                            Aging is associated with sarcopenia, a significant
                                                shown that satellite cells themselves are also able to                        decline in the mass, strength, and endurance of skeletal
                                                differentiate into both osteogenic and adipogenic (but                        muscles in both human and animal models (Karakelides
                                                not hematopoietic) lineages under standard cell culture                       and Nair 2005). It has been proposed that compro-
                                                conditions (Asakura et al. 2001; Shefer et al. 2004) or                       mised satellite cell function contributes to this age-linked
                                                following exposure to osteogenic- (BMP2) or adipogenic-                       muscle deterioration. Whether satellite cell numbers de-
                                                inducing factors (Asakura et al. 2001; Wada et al.                            cline with age is controversial and probably varies among
                                                2002). It is still unclear if these alternative satellite cell                different muscles and species (e.g., Schafer et al. 2005;



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                                                1184                                                                                                      Zammit, Partridge, Yablonka-Reuveni

                                                Shefer et al. 2006). Similarly, the amount of prolifera-                    primary cultures and clonal cultures prepared from
                                                tion that they can undergo has also been proposed to                        chicken and mouse, myogenic cells proliferate and co-
                                                vary with age (reviewed in Mouly et al. 2005). The age-                     express Pax7 and MyoD but, with time, cells express-
                                                linked decline in the rapidity at which satellite cells can                 ing Pax7 but not MyoD begin to accumulate. Rare
                                                be recruited into myogenesis clearly has an impact on                       satellite cells can be found in which the progeny of
                                                satellite cell performance (Conboy et al. 2003) but may                     a recent division have MyoD distributed asymmetri-
                                                be due more to a delay of entry into proliferation and not                  cally, with one satellite cell lacking expression, possi-
                                                necessarily an inherent declining capacity to differentiate                 bly indicating a divergence in the fate of the two
                                                (Shefer et al. 2006).                                                       progeny (Zammit et al. 2004b). Certainly the absence
                                                   That said, exposure of myogenic progenitors from old                     of MyoD also causes satellite cells to continue to
                                                muscle to a young environment rejuvenates the capacity                      proliferate and delay differentiation (Sabourin et al.
                                                of progenitors to contribute to repair (Carlson and                         1999; Yablonka-Reuveni et al. 1999a). The role of
                                                Faulkner 1989; Carlson et al. 2001; Conboy et al. 2005)                     MyoD in control of these cell fate decisions is central
                                                indicating that (some?) satellite cells do not change                       to muscle regeneration, yet the mechanism remains
The Journal of Histochemistry & Cytochemistry




                                                significantly with age. A reduction in the numbers of                       poorly understood.
                                                functional satellite cells along with a declining systemic                     In the absence of Pax7, satellite cells in mutant mice
                                                environment and intramuscular changes in innervation                        are rapidly depleted during the early postnatal period,
                                                and vascularization together may underlie failure of old                    showing that Pax7 has a crucial role in satellite cell
                                                muscles to repair properly following injury and during                      function (Seale et al. 2000; Oustanina et al. 2004;
                                                routine muscle utilization (Grounds 1998).                                  Kuang et al. 2006; Relaix et al. 2006). Whether the
                                                                                                                            absence of Pax7 causes a failure of self-renewal, how-
                                                                                                                            ever, is debatable. Constitutively expressed Pax7 is
                                                Is the Satellite Cell Compartment Maintained by                             compatible with MyoD expression, proliferation, and
                                                Self-renewal?                                                               myogenic differentiation (Relaix et al. 2006; Zammit
                                                The classic view that satellite cells self-renew, entailing                 et al. 2006 but see Olguin and Olwin 2004). Because
                                                either a stochastic event or an asymmetrical cell division                  infection of wild-type myoblasts with a dominant neg-
                                                at some point where one daughter cell is committed to                       ative form of Pax7 leads to massive cell death, Pax7
                                                differentiation whereas the second continues to prolif-                     may have anti-apoptotic functions and therefore play
                                                erate or becomes quiescent, was initially proposed                          a role in maintenance and survival rather than self-
                                                by Moss and Leblond (1971) over 30 years ago. When                          renewal (Relaix et al. 2006). As Pax7 also has a role
                                                myoblast cultures are exposed to low serum medium,                          in neurogenesis and is expressed in adult brain, its
                                                most respond by differentiating. However, some stop                         deletion in vivo could also have indirect effects on
                                                cycling and downregulate MyoD expression, charac-                           muscle, meaning that conditional deletion of Pax7 in
                                                teristic of quiescence (Kitzmann et al. 1998; Yoshida                       adult muscle would be useful to specifically dissect its
                                                et al. 1998). These ‘‘reserve cells’’ re-appear after clon-                 role in satellite cells. Another consideration is that Pax3
                                                ing, indicating that it is a cell-intrinsic property and                    has been shown to control cell surface properties during
                                                may reflect a stage in the cell cycle that leads to quies-                  development (Mansouri et al. 2001). Loss of another
                                                cence rather than differentiation when challenged with                      member of the paired box transcription factor family
                                                mitogen withdrawal, rather than having a genetic, line-                     Pax6 in the developing forebrain results in altered cel-
                                                age basis (Baroffio et al. 1996; Yoshida et al. 1998).                      lular adhesion and expression of R-cadherin (Stoykova
                                                    Culturing isolated myofibers in suspension provides                     et al. 1997). Therefore, effects of Pax7 deletion may
                                                a model that is a hybrid between in vivo regeneration                       well also perturb satellite cell function by affecting
                                                and culture of dissociated single cells. Using this system,                 cell surface and consequently cell adhesion and/or cell–
                                                we have recently shown that satellite cell progeny adopt                    cell interactions.
                                                divergent fates. In culture, satellite cells synchronously                     Another possible candidate to control satellite cells is
                                                activate to coexpress Pax7 and MyoD before dividing.                        Notch signaling, which is involved in the decision of
                                                The majority then suppress Pax7 expression, maintain                        satellite cells to stop proliferating (Conboy and Rando
                                                MyoD, and differentiate, whereas others downregulate                        2002). The inhibitor of Notch, Numb, is asymmetri-
                                                MyoD, maintain Pax7, and eventually stop cycling,                           cally distributed after cell division in some satellite cell
                                                entering a state resembling quiescence but can be re-                       progeny (Conboy and Rando 2002) and appears to
                                                stimulated and will again divide and differentiate                          segregate with Pax7 (Shinin et al. 2006), indicating that
                                                (Zammit et al. 2004b). A similar diversification in sat-                    it may influence cell fate with a mechanism similar to
                                                ellite cell fate, with some cells Fopting out_ of immediate                 that used in Drosophila development. Certainly with
                                                differentiation, has also been described during post-                       age, failure of the Notch pathway appears to contribute
                                                hatch chicken development (Halevy et al. 2004) and in                       to the general reduction in efficiency of muscle regen-
                                                the adult and aging mouse (Shefer et al. 2006). In both                     eration (Conboy et al. 2003).



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                                                The Satellite Cell: The Preeminent Muscle Stem Cell                                                                               1185

                                                    Transplantation of cells into muscle provides a                         produced by exon skipping forming an in frame tran-
                                                useful assay for their fate in vivo. Much as stem cell                      script (Hoffman et al. 1990). These revertant fibers
                                                function in the hematopoetic lineage has been explored                      occur as singletons in newborn mdx mice but are then
                                                using transplantation following whole-body irradiation                      found as clusters that increase in constituent fiber num-
                                                to destroy endogenous stem cells, a similar assay of                        ber with age (Yokota et al. 2006). Because each cluster
                                                transplantation into locally irradiated muscle has been                     is composed of myofibers with an identical pattern
                                                used to analyze the potential of myogenic precursor                         of exon skipping often distinct from neighboring rever-
                                                cells (e.g., Collins et al. 2005). Based on transplantation                 tant clusters (Lu et al. 2000), this progressive accumu-
                                                models, it has long been known that grafted myogenic                        lation of myofibers in a contiguous group containing
                                                cells not only contribute myonuclei but also produce                        this de facto heritable marker is consistent with a
                                                myogenic precursors that can be re-activated by muscle                      clonogenic event (Yokota et al. 2006). Although it is
                                                damage, will proliferate and differentiate ex vivo, and                     possible that the rare genetic event that results in the
                                                form new muscle after serial transplantations (Watt                         revertant fiber may have occurred during development
                                                et al. 1982; Partridge et al. 1989; Yao and Kurachi                         in a presatellite cell, it is likely that Fgrowth_ of the
The Journal of Histochemistry & Cytochemistry




                                                1993; Morgan et al. 1994; Gross and Morgan 1999;                            cluster is a satellite cell-mediated event requiring ex-
                                                Cousins et al. 2004). More recently, it has been shown                      tensive proliferation and possibly self-renewal of these
                                                that these donor-derived myogenic precursors can oc-                        exceptional satellite cells.
                                                cupy the satellite cell niche and remain undifferentiated,
                                                retaining the ability to proliferate in response to future
                                                stimuli (Blaveri et al. 1999; Heslop et al. 2001). In these                 Is There a Resident Satellite Cell–Stem Cell in
                                                experiments, large numbers of muscle-derived cells were                     Muscle Tissue?
                                                grafted (2–5 3 105). Therefore, the exact nature of the                     Satellite cell self-renewal may not be the sole mecha-
                                                cells is unknown, as to whether they proliferate before                     nism used to maintain a viable regenerative compart-
                                                entering the satellite cell niche, i.e., self-renew. To ad-                 ment. It has been proposed that, once activated, most
                                                dress these points, we have now grafted a single myo-                       satellite cells in healthy adult muscle are committed to
                                                fiber, which has the advantage of having only a small                       myogenic differentiation (e.g., Yablonka-Reuveni and
                                                number of associated satellite cells. For example, a sin-                   Rivera 1997) and so require replenishment from a non-
                                                gle EDL myofiber with a mean of approximately seven                         satellite progenitor cell. In this scenario, there may be a
                                                satellite cells can give rise to considerable amounts of                    progenitor of satellite cells residing outside of the satel-
                                                new muscle and, importantly, many new functional sat-                       lite cell niche. Such a progenitor could be a multipotent
                                                ellite cells. Because the number of new myonuclei and                       stem cell able to give rise to several differentiated cell
                                                satellite cells far exceeds the number implanted with                       types including satellite cells. Candidates for this resi-
                                                the single myofiber, satellite self-renewal must have oc-                   dent ‘‘stem cell of satellite cells’’ include endothelial-
                                                curred (Collins et al. 2005). Even taking into account                      associated cells (De Angelis et al. 1999), interstitial cells
                                                any mitogenic effects of an irradiated muscle host en-                      (Tamaki et al. 2002; Polesskaya et al. 2003; Kuang
                                                vironment, this is still a significant amount of prolifer-                  et al. 2006), and side population (SP) cells (Gussoni
                                                ation (Morgan et al. 2002). Satellite self-renewal may                      et al. 1999; Asakura and Rudnicki 2002).
                                                be limited to a subpopulation of satellite cells and not                        Mesonagioblasts, stem cells derived from the devel-
                                                necessarily be a property of all (Beauchamp et al. 1999).                   oping vasculature (Minasi et al. 2002), are able to res-
                                                This is consistent with recent observations that a limited                  cue a-sarcoglycan2/2 adult muscle (Galvez et al. 2006)
                                                number of satellite cells retain incorporated BrdU in                       and also occupy the satellite cell niche after transplan-
                                                adult muscle from a pulse delivered perinatally. Some of                    tation (Sampaolesi et al. 2003). Primary endothelium
                                                these satellite cells do not then segregate the label upon                  from developing/postnatal mice, and to a lesser extent
                                                cell division. Together this was interpreted as evidence                    adult mice, and cell lines derived from vasculature
                                                that these particular satellite cells are stem cells with                   smooth muscle can also give rise to myogenic cells
                                                non-equivalent genomic DNA strands where one tem-                           (Graves and Yablonka-Reuveni 2000; Cusella De
                                                plate strand is being protected from DNA replication                        Angelis et al. 2003), leading to the suggestion that
                                                errors (Shinin et al. 2006).                                                these structures may be a source of satellite cells. Con-
                                                    Finally, the phenomenon of the revertant fiber                          sistent with this is the observation that endothelium and
                                                provides further evidence that satellite cell self-renewal                  satellite cells have certain molecular markers in com-
                                                is part of normal muscle homeostasis. The mdx mouse                         mon such as CD34 (De Angelis et al. 1999; Beauchamp
                                                is a genetic and biochemical model of Duchenne mus-                         et al. 2000), and that myogenic and endothelial cells
                                                cular dystrophy, which lacks dystrophin protein due to                      probably share a common embryonic precursor (Kardon
                                                a non-sense point mutation (Bulfield et al. 1984). De-                      et al. 2002). Indeed, multipotent CD45-ve/CD341ve/
                                                spite this translational block, rare revertant fibers can                   Sca11ve cells able to generate both myogenic and
                                                be observed, containing truncated dystrophin species                        endothelial cells are located in the muscle interstitium



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                                                1186                                                                                                        Zammit, Partridge, Yablonka-Reuveni

                                                (Tamaki et al. 2003). More recently, it has also been                         2005). Interestingly, some satellite cell progeny in cul-
                                                shown that Pax3 can identify interstitial cells with myo-                     ture express Sca1 (Mitchell et al. 2005), a phenomenon
                                                genic potential (Kuang et al. 2006), but their relation-                      whose relevance to in vivo myogenesis is unknown. The
                                                ship to other interstitial cells remains to be established.                   relationship, if any, of these various populations of cells
                                                    SP cells were first identified as bone marrow-derived                     to each other and, crucially, to satellite cells, remains to
                                                multipotent hematopoetic stem cells characterized by                          be determined.
                                                their ability to efflux the vital DNA dye Hoechst 33,342
                                                (Goodell et al. 1996). Cells with similar physical prop-
                                                erties can also be isolated directly from muscle (Gussoni                     Is the Satellite Cell Pool Replenished From
                                                et al. 1999; Jackson et al. 1999). Upon transplantation,                      Outside Muscle Tissue?
                                                muscle SP cells are able to contribute to both the hema-                      Grounds (1983) reported that skeletal muscle precur-
                                                topoietic (though poorly) and muscle lineages, produc-                        sors do not arise from transplanted bone marrow.
                                                ing both dystrophin-expressing myofibers in mdx mice                          Fifteen years later, it was shown that muscle can be
                                                and cells occupying the satellite cell niche (Gussoni et al.                  formed from this source (Ferrari et al. 1998). The dif-
The Journal of Histochemistry & Cytochemistry




                                                1999; Asakura and Rudnicki 2002). Interestingly,                              ference in the two studies was the assay method used.
                                                muscle SP cells appear to be unable to adopt a myogenic                       Because sensitive molecular markers of donor cells
                                                lineage fate in culture in the absence of myogenic cells                      were still several years away, Grounds (1983) had to
                                                (but see Schienda et al. 2006). Muscle SP cells are a                         rely on testing for the presence of a donor-specific
                                                heterogeneous population, so far lacking a coherent set                       isoenzyme in muscle extracts using gel electrophoresis,
                                                of molecular markers presumably because the condi-                            requiring a substantial amount of muscle to be made.
                                                tions used for their fluorescence-activated cell sorting                      Ferrari et al. (1998) were able to use a sensitive nlacZ
                                                (FACS) isolation (e.g., enzymatic digestion conditions                        reporter gene, enabling individual donor-derived nuclei
                                                used prior to FACS and/or concentration of Hoechst                            to be identified.
                                                dye) dictate the range of cells included in the SP fraction                      Following bone marrow transplants, it has been
                                                (Montanaro et al. 2004; Rivier et al. 2004). It does                          shown that bone marrow-derived cells can be found in
                                                appear, though, that the majority of muscle SP cells                          association with myofibers and express satellite cell
                                                express Sca1 but not CD45 (Montanaro et al. 2004).                            markers (LaBarge and Blau 2002; Dreyfus et al. 2004;
                                                Most muscle SP cells comprise a resident population                           but see Wernig et al. 2005). Interestingly, mesenchymal
                                                (Rivier et al. 2004), and recent evidence points to a                         cells from synovial membrane/fluid are also able to
                                                large proportion of them being derived from cells in the                      occupy the satellite cell niche (De Bari et al. 2003).
                                                hypaxial myotome that express Pax3, the same source                           Occupation of the satellite cell niche, albeit inefficiently,
                                                as satellite cells (Schienda et al. 2006). Further studies                    has lead to the assumption that any host myofiber
                                                are required to establish whether SP and satellite cells                      with a donor contribution is a result of incorporation of
                                                develop in parallel or whether one population is ac-                          these donor-derived cells. Recently, however, Sherwood
                                                tually the progeny of the other.                                              et al. (2004) have shown that only satellite cells
                                                    Other populations of cells with myogenic potential                        occupying the satellite cell niche are functional as
                                                can also be isolated from muscle tissue. Both CD451/                          myogenic precursors, and that the niche appears unable
                                                2ve and Sca11/2ve muscle-derived cells are able                               to instruct other cell types such as bone marrow-derived
                                                to become incorporated into myofibers and express a                           cells to function in a similar manner to satellite cells
                                                muscle-specific transgene (McKinney-Freeman et al.                            (Sherwood et al. 2004). Indeed, cells isolated from a
                                                2002), although only the CD451ve ones have hema-                              variety of tissues including thymus (Pagel et al. 2000),
                                                topoetic potential. CD451ve/Sca11ve cells isolated                            nerve (Courbin et al. 1989), brain (Tajbakhsh et al.
                                                from damaged, but not uninjured, muscle are able to                           1994; Galli et al. 2000; Rietze et al. 2001), and others
                                                adopt a myogenic fate directed by Wnt signaling and                           (comprehensively reviewed in Grounds et al. 2002)
                                                via a Pax7-dependent process (Polesskaya et al. 2003;                         have all been shown to generate skeletal muscle in vitro
                                                Seale et al. 2004). Finally, multipotent cell lines have                      and, in some cases, also in vivo. How and why this
                                                been isolated from muscle tissue using preplating                             occurs, though, is not clear. Certainly, cells are able
                                                techniques (e.g., Lee et al. 2000).                                           to directly fuse with myofibers without first adopting
                                                    Notably though, the cell populations discussed in                         a satellite cell-like cell intermediary step (Grounds
                                                this section have only been characterized following pu-                       et al. 2002). Myelomonocytic precursor cells are able
                                                rification from muscle tissue, such as by FACS. CD45                          to directly incorporate into regenerating myofibers
                                                and Sca11ve cells are widespread in muscle. For exam-                         (Camargo et al. 2003) where the syncytial nature of the
                                                ple, Sca1 is present on cells in blood vessels, but in quies-                 myofiber environment may re-program their nuclei,
                                                cent satellite cells .99% do not express Sca1, whereas                        as shown for heterokaryons (Blau et al. 1985). It should
                                                CD45 is not expressed at all (Zammit and Beauchamp                            be noted, however, that a large proportion of bone
                                                2001; Asakura and Rudnicki 2002; Mitchell et al.                              marrow-derived cells incorporating into myofibers do



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                                                The Satellite Cell: The Preeminent Muscle Stem Cell                                                                              1187

                                                not actually activate the myogenic program (Lapidos                        of a physiologically relevant system for muscle repair
                                                et al. 2004; Wernig et al. 2005).                                          or merely reflect some imprecision in the mechanisms
                                                   The nature of cells with myogenic potential in non-                     that determine the fate of precursor cells remains to
                                                muscle tissues has remained elusive, and their biological                  be determined.
                                                role, if any, is unclear. Bone marrow cells can home to                       As more genetic mouse models become available for
                                                muscle but not to any significant degree, with the best                    tracing or abolishing satellite cells in vivo, it might be
                                                engraftment following bone marrow transplantation in                       possible to address several long-standing questions re-
                                                the order of 5%, but the majority of muscles exhibit                       garding fundamental aspects of satellite cell biology.
                                                much lower levels (Brazelton et al. 2003; Wernig et al.                    For example, how frequently are satellite cells required
                                                2005). Importantly, continual recruitment from the                         to supply new myonuclei during normal muscle uti-
                                                transplanted bone marrow is not significant, because                       lization (Spalding et al. 2005)? Perhaps satellite cell
                                                the number of myofibers with a donor contribution                          self-renewal and asymmetrical cell division are compro-
                                                quickly plateau in normal muscle and do not increase                       mised in aged adult muscle, resulting in the observed
                                                significantly with time (LaBarge and Blau 2002; Wernig                     decline in satellite cells (Shefer et al. 2006). Likewise,
The Journal of Histochemistry & Cytochemistry




                                                et al. 2005), even in mdx mice whose muscles undergo                       despite the common notion that satellite cells partic-
                                                chronic cycles of myofiber degeneration and regenera-                      ipate in muscle hypertrophy as a result of exercise
                                                tion (Ferrari et al. 2001). Similarly, in man, a Duchenne                  and weight overload, understanding of this field has
                                                muscular dystrophy patient who underwent a bone                            progressed slowly since the initial observations by
                                                marrow transplant still had only ,1% of myofibers                          Schiaffino et al. (1976). Furthermore, the satellite cell
                                                with donor-derived nuclei 13 years later (Gussoni et al.                   niche is thus far a term without a base – is the region
                                                2002). Presumably, therefore, no significant slowing in                    where the satellite cell resides on the myofiber surface
                                                the progression of the disease was demonstrated.                           different from that surrounding it? Does the basement
                                                Furthermore, there does not appear to be much traf-                        membrane in that area have unique features that di-
                                                ficking between bone marrow and muscle SP even after                       rect the regulation of satellite cells? Does the myo-
                                                overt muscle injury (McKinney-Freeman et al. 2003;                         fiber itself exert control over the quiescent vs active
                                                Rivier et al. 2004), although such damage does appear                      state of the satellite cell? Can donor satellite cells be
                                                to recruit further bone marrow-derived cells to myo-                       modified so they participate in muscle repair along with
                                                fibers (Wernig et al. 2005).                                               self-renewal for the purpose of combating muscle de-
                                                                                                                           terioration in aging, muscular dystrophies, and as a
                                                                                                                           consequence of diseases including cancer and AIDS?
                                                Conclusions                                                                Finally, can we better understand the role of the non-
                                                The discovery of the satellite cell in 1961 provided the                   satellite cell myogenic sources discussed here and whether
                                                obvious candidate for the source of new muscle growth                      they reflect a normal process. Although non-satellite cell
                                                and repair. It remained the uncontested myogenic pro-                      sources might not be of significance to muscle repair
                                                genitor of skeletal muscle until a series of articles dem-                 under normal conditions, can they be recruited for en-
                                                onstrated that cells other than satellite cells could                      hancing myogenic stem cell function and myofiber main-
                                                contribute to myogenesis. This led some to question this                   tenance in disease and aging? As much as 1961 defined
                                                classic view that satellite cells are the sole supply of                   the parameters in which the biology of adult muscle
                                                myogenic precursors during the life span of the animal.                    would be explored for the rest of the 20th century, the
                                                The contribution of these non-satellite cells to muscle in                 opening years of the new millennium are providing us
                                                any case is very low and may well be unnecessary,                          with new paradigms of adult myogenesis. Will these
                                                considering the large amount of new muscle and viable                      new models redefine the mechanisms of muscle growth
                                                satellite cells that can be generated from the few satel-                  and regeneration, or will they send us back to the future
                                                lite cells resident on a single transplanted myofiber                      of 1961?
                                                (Zammit et al. 2002; Collins et al. 2005). When the
                                                endogenous satellite cell compartment is rendered in-                      Acknowledgments
                                                capable of proliferation by localized irradiation, muscle                     The authors acknowledge current support without which
                                                regeneration is effectively prevented, indicating that                     this work could not be possible. P.S.Z. and T.A.P. received
                                                circulating cells with myogenic potential are not able                     funding from the Medical Research Council (UK). Z.Y-R. re-
                                                to contribute significantly and certainly not able to                      ceived support from the National Institutes of Health (Grants
                                                demonstrably affect muscle function (Wakeford et al.                       AG-21566 and AG-13798) and from the United States De-
                                                1991; Heslop et al. 2000). Although lethally irradiated                    partment of Agriculture, Cooperative State Research, Edu-
                                                                                                                           cation, and Extension Service (National Research Initiative,
                                                mice can be rescued by transplantation with hemato-                        Competitive Grant #2003-35206-12843).
                                                poetic stem cells, these cells do not appear to be able                       We thank Dr. Charlotte Collins and Dr. Jennifer Morgan
                                                to become functional satellite cells (Sherwood et al.                      (Imperial College, London, UK) and Dr. Irina Kirillova
                                                2004). Whether non-satellite cells even constitute part                    (University of Washington, Seattle, WA) for comments on



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                                                1188                                                                                                               Zammit, Partridge, Yablonka-Reuveni

                                                the manuscript. We are grateful to Dr. Benjamin Rosser                                  young and old rats: age of host determines recovery. Am J Physiol
                                                and Dr. Mohammed Allouh (University of Saskatchewan,                                    256:C1262–1266
                                                Saskatoon, Canada), Dr. J. David Rosenblatt (Toronto, Can-                           Charge SB, Rudnicki MA (2004) Cellular and molecular regulation
                                                ada), and Dr. Jonathan Beauchamp (Imperial College,                                     of muscle regeneration. Physiol Rev 84:209–238
                                                                                                                                     Christ B, Jacob HJ, Jacob M (1975) Autoradiographic studies
                                                London, UK) for providing images. P.S.Z. would like to dedi-                            on somite formation in the chick embryo. Verh Anat Ges 69:
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The Journal of Histochemistry & Cytochemistry




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