Article |
Address correspondence to Michael A. Rudnicki, Molecular Medicine Program, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa, Ontario, K1H 8L6 Canada. Tel.: (613) 739-6740. Fax: (613) 737-8803. E-mail: mrudnicki{at}ohri.ca
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: stem cell; satellite cell; Pax7; hematopoiesis; Sca-1
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Satellite cells have long been considered monopotential stem cells with the ability to only give rise to cells of the myogenic lineage. However, recent experiments have identified the existence of adult stem cells present in most (if not all) tissues that appear to exhibit the ability to differentiate into many different cell types after reintroduction in vivo. This work has raised important questions regarding the developmental potential of stem cells derived from diverse tissues including muscle, bone marrow, and brain (Seale et al., 2001). For example, hematopoietic stem cells (HSCs),* in addition to their ability to produce all blood cell lineages, also exhibit developmental plasticity when introduced into different tissues. HSCs can differentiate into hepatic cells (Lagasse et al., 2000), cardiac muscle and vascular endothelium (Jackson et al., 2001), and several epithelial cell types (Krause et al., 2001) after transplantation. Therefore, many or all tissues appear to contain a population of adult stem cells that differentiate in a context-specific manner, presumably in response to growth factors and signals provided by their host tissues (Seale et al., 2001).
Satellite cells are believed to be the committed stem cell of the myogenic cells responsible for the postnatal growth and regeneration of muscle (Seale et al., 2001). The notion that satellite cells exclusively accomplish the regeneration of adult muscle has been challenged by the demonstration that muscle also contains a population of adult stem cells, called muscle-derived stem cells. Muscle-derived stem cells exhibit the capacity to reconstitute the entire hematopoietic repertoire after intravenous injection into lethally irradiated mice (Jackson et al., 1999; Kawada and Ogawa, 2001). Muscle-derived stem cells isolated by FACS® of side population (SP) cells, on the basis of Hoechst dye exclusion, exhibit the capacity to give rise to hematopoietic cells after intravenous injection into lethally irradiated mice. In addition, transplanted SP cells isolated from bone marrow or muscle actively participate in the formation of skeletal myotubes during regeneration (Gussoni et al., 1999). Importantly, Pax7-deficient muscle entirely lacks myogenic satellite cells, yet contains muscle SP cells that exhibit a high level of hematopoietic progenitor activity (Seale et al., 2000). Together, these data demonstrate that muscle-derived stem cells represent a distinct cell population from satellite cells. These studies suggested the hypothesis that induction of Pax7 in muscle-derived stem cells induces satellite cell specification by restricting alternate developmental programs. However, direct proof that muscle-derived stem cells represent the progenitors of satellite cells and any understanding of the mechanisms that regulate this developmental step remains lacking.
To investigate the relationship between muscle-derived stem cells and myogenic satellite cells, we used a variety of cell culture assays as well as in vivo intramuscular transplantation to explore their developmental potential. Our experiments demonstrate that the ability of muscle-derived stem cells to undergo myogenic specification is a regulated process that appears to involve cell-mediated inductive interactions.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Satellite cells do not exhibit hematopoietic potential
Satellite cells have long been considered monopotential stem cells, with the ability to only give rise to cells of the myogenic lineage. However, recent experiments have indicated that satellite cells readily differentiate into different cell types such as osteocytes and adipocytes (Asakura et al., 2001). To investigate whether satellite cells have the potential to differentiate into hematopoietic cells, we cultured single muscle fibers from heterozygous Myf5-nlacZ mice in Methocult M3434. The expression of Myf5-nlacZ recapitulates the expression of the endogenous Myf5 mRNA both during embryogenesis (Tajbakhsh et al., 1996) and in adult muscle (Beauchamp et al., 2000). Isolated muscle fibers maintained in culture for 14 d gave rise to colonies uniformly composed of Myf5-nlacZpositive multinucleated, contractile myotubes (Fig. 2, AD). Importantly, hematopoietic colonies were never detected in these long-term cultures of isolated muscle fibers (Fig. 2 E; n = 180 fibers). By contrast, 1030 hematopoietic colonies were formed after plating of 1 x 104 unfractionated muscle cell suspension. The inability of satellite cells to undergo hematopoietic differentiation and the preferential differentiation of Myf5-nlacZexpressing cells into muscle (Fig. 2 C) strongly support the hypothesis that satellite cells are restricted in their developmental potential within the mesenchymal range of cell lineages.
Muscle SP cells in vitro undergo hematopoietic but not myogenic differentiation
The expression of Myf5-nlacZ was readily detected in the nuclei of satellite cells on freshly isolated muscle fibers (Fig. 2 A; Beauchamp et al., 2000). A similar expression profile of lacZ within myonuclei and satellite cell nuclei was also observed in single muscle fiber cultures prepared from MD6.0-lacZ transgenic mice carrying myoD upstreamdriving lacZ gene (Asakura et al., 1995; unpublished data). Therefore, if purified muscle SP cells (a fraction of muscle-derived stem cells) contained a fraction of satellite cells, Myf5-nlacZ or MD6.0-lacZexpressing cells should be detected within the SP compartment. To test this possibility, we used the FACS®/Hoechst method (5 µg/ml Hoechst 33342) to fractionate muscle cell suspensions into SP and main population (MP). Compared to bone marrowderived SP cells (a fraction of HSCs), increased numbers of SP cells were detected in muscle (0.2 vs. 2.3% of total cells; Fig. 3 A). Similar results were obtained when skeletal muscle cells were stained with 12.5 µg/ml Hoechst 33342 (unpublished data) as described previously (Gussoni et al., 1999). Both bone marrow and muscle SP cells stained with Hoechst dye were sensitive to verapamil, which is consistent with reported results (Jackson et al., 1999). Recent studies have demonstrated stem cells derived from skeletal muscle that exhibit hematopoietic potential express the hematopoietic marker CD45 and Sca-1 (Kawada and Ogawa, 2001; McKinney-Freeman et al., 2002). To investigate the origin of the hematopoietic progenitors in muscle SP cells, FACS® analysis was used to subfractionate muscle SP cells with CD45 and Sca-1 antibodies. Most of the muscle SP cells (92%) expressed Sca-1, which is consistent with previous observation (Gussoni et al., 1999). 16% of muscle SP cells expressed CD45 consisting of both Sca-1positive (9.2%) and negative (6.8%) fractions (Fig. 3 B). Next, sorted cells (MP and SP) and unfractionated whole population (WP) cells prepared from Myf5-nlacZ or MD6.0-lacZ mouse muscle were stained with X-gal. Both WP and MP cells contained a similar proportion of lacZ-expressing cells (Fig. 3 C). By contrast, the SP fraction did not contain any cells that expressed Myf5-nlacZ or MD6.0-lacZ. Desmin and Pax7 are also known to be expressed in both quiescent satellite cells and derivative myoblasts in adult muscle (Seale et al., 2000). Importantly, no desmin or Pax7 expression was detected in cells from the muscle SP fraction (unpublished data). Therefore, satellite cells and their daughter myoblasts strictly reside within the MP fraction of cells by FACS®/Hoechst analysis.
|
|
Sca-1positive cells are located outside of muscle fibers
To further confirm that muscle SP cells are distinct cell population from satellite cells, we first examined detection of HSC markers CD34, Sca-1, and CD45, in satellite cells on freshly isolated muscle fibers. Immunohistochemical detection clearly demonstrated that CD34 was expressed in satellite cells on muscle fibers (Fig. 5 A). About three to four CD34-expressing satellite cells were normally detected per muscle fiber (unpublished data), which is consistent with previous observation (Beauchamp et al., 2000). By contrast, satellite cells on muscle fibers were never observed to express Sca-1 or CD45 (n = 20 fibers; Fig. 5 A). Previously, it has been reported that the majority of muscle SP cells express Sca-1, an important cell surface marker for HSCs (Gussoni et al., 1999; Jackson et al., 1999). To examine where Sca-1expressing cells are located within muscle, double immunostaining was performed. Clearly, Sca-1positive cells were located outside of the muscle fiber basal lamina as revealed by staining with antilaminin antibodies (Fig. 5 B). In addition, Sca-1expressing cells were frequently detected closely juxtaposed to blood vessels as well as endothelium that expressed PECAM (Fig. 5 B). Similar results were reported in previous works in which Sca-1positive cells were detected in endothelium and outer layer of blood vessels, but were not detected beneath the basal lamina of skeletal muscle fibers (Zammit and Beauchamp, 2001). These results further confirm that muscle-derived stem cells are distinct cell population from satellite cells and may be associated with the vasculature within muscle.
|
|
Muscle SP cells undergo myogenic specification after co-culture with primary myoblasts
Intramuscular transplantation experiments suggest that muscle-derived stem cells undergo myogenic specification via a myocyte-mediated inductive interaction. To investigate whether cell-mediated interactions could influence the developmental fate of muscle SP cells in vitro, we co-cultured FACS®/Hoechst-purified muscle SP cells from ROSA26 mice, expressing lacZ protein ubiquitously (Zambrowicz et al., 1997), with equal numbers of myoblasts or fibroblasts. Immunohistochemistry for desmin was performed to confirm the differentiation of lacZ-expressing ROSA26 cells into myocytes. Culture of muscle SP cells alone resulted in the formation of any lacZ-expressing myogenic cells (Fig. 7 A). By contrast, co-culture of muscle SP cells with primary myoblasts resulted in the formation of multinucleated myotubes that coexpressed lacZ and desmin. The number of nuclei of myogenic cells that coexpressed desmin and lacZ was 3.8% (n = 4) of the total lacZ-expressing ROSA26 cell nuclei. We also observed myogenic conversion in co-cultures of muscle SP cells with C2C12 myoblasts but not with C3H10T1/2 fibroblasts or conditioned medium from primary myoblast cultures (unpublished data). We also co-cultured 1 x 104 FACS®/Hoechst-purified muscle SP cells from TgN(GFPU)5-Nagy (GFP) mice, expressing a GFP ubiquitously (Hadjantonakis et al., 1998), with equal numbers of primary myoblasts. Immunohistochemistry for MHC was performed to confirm the differentiation of GFP-expressing muscle SP cells into muscle cells after co-culture with primary myoblasts (Fig. 7 B). Finally, co-culture of muscle SP cells isolated from Myf5-nlacZ mice with primary myoblasts resulted in the formation of Myf5-nlacZexpressing mononuclear myoblasts and multinucleated myotubes (Fig. 7 C), indicating that muscle SP cells did not simply form heterokaryon myotubes fused with primary myoblasts. By contrast, we failed to detect any muscle differentiation of bone marrow SP cells after co-culture with primary myoblasts (unpublished data), suggesting that there is a biological difference between muscle and bone marrow SP cells. Together, these data unequivocally demonstrate that some portion of muscle SP undergoes myogenic specification after co-culture with primary myoblasts.
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Importantly, myogenic specification of muscle SP cells and the formation of mononuclear myoblasts were observed to occur in vitro after co-culture with primary myoblasts. In addition, muscle SP cells contain at least two distinct fractions with myogenic potential as CD45- mSP and CD45+ mSP. Both exhibit the potential to give rise to myogenic cells after co-culture with primary myoblasts. Recent work demonstrated that both intramuscular and intravenous transplantation of bone marrow and intravenous transplantation of bone marrow SP cells contributed to skeletal muscle fiber formation (Ferrari et al., 1998; Gussoni et al., 1999; Fukada et al., 2002). More recently, it has been demonstrated that muscle-derived CD45-positive cells integrate into regenerating muscle fibers after intramuscular injection (McKinney-Freeman et al., 2002). By contrast, we have observed that CD45- mSP cells have the potential to give rise to adipocytes and osteocytes after induction (unpublished data). Therefore, it is interesting to hypothesize that the CD45- mSP fraction of cells contains progenitor cells that are similar to multipotential mesenchymal stem cells (Pittenger et al., 1999).
Interestingly, muscle SP prepared from Pax7-/- mice, when co-cultured with primary myoblasts, also resulted in the formation of multinucleated myotubes. In addition, forced expression of MyoD could induce myogenic differentiation of Pax7-/- muscle SP cells. Furthermore, Pax7 could not be induced by MyoD in myoblasts derived from wild-type muscle SP cells. Therefore, these data suggest that terminal myogenic differentiation of muscle-derived stem cells is a Pax7-independent process and that Pax7 functions upstream of MyoD during satellite cell development.
Muscle SP cells differentiated into myocytes and formed new myofibers after intramuscular injection into regenerating muscle. Therefore, the observed Pax7-independent myogenic differentiation of muscle SP cells suggests that Pax7 is required for the specification of satellite cells, but not for terminal myogenic differentiation. Together, these data indicate that muscle-derived stem cells are competent for induction of myogenic specification as well as for direct myogenic differentiation. The inability of muscle SP cells to undergo myogenic specification except in the presence of myogenic cells suggests that the process is subject to regulation via a mechanism that involves cell-mediated inductive interactions.
Primary myoblasts derived from neonatal mice readily give rise to satellite cells after intramuscular injection (Heslop et al., 2001). Muscle SP cells have been suggested to differentiate into satellite cells based on their location after intravenous injection into irradiated mice (Gussoni et al., 1999). Furthermore, fetal liver and bone marrow cells have a potential to differentiate into satellite cells based on the location after injection into busulphan-treated neonatal mice (Fukada et al., 2002). Here, we demonstrate that muscle SP cells have the potential to differentiate into satellite cells after intramuscular injection into regenerating muscle. These satellite cells express satellite cell markers Myf5-nlacZ, Pax7, and desmin, and are proliferative in vitro, suggesting that muscle SP cells can differentiate into functional satellite cells. The in vivo potential of muscle SP cells that give rise to satellite cells supports our hypothesis that at least some portion of satellite cells originates from muscle-derived stem cells. However, it remains unclear whether both CD45- mSP and CD45+ mSP have the potential to give rise to satellite cells after intramuscular transplantation. In addition, it remains to be elucidated whether Pax7 is required for muscle SP cells to differentiate into satellite cells after intramuscular transplantation. We are currently investigating these questions.
An important outstanding question concerns the location of muscle-derived stem cells within skeletal muscle. Examination of regeneration in dystrophic muscle has revealed that recruitment of cells via the circulatory system does not provide a substantial source of myoblasts for muscle repair after radiation of mouse limbs (Heslop et al., 2000). It is conceivable that the vascular-associated progenitors of myogenic satellite cells in the embryo persist in close association with the vasculature as adult stem cells in skeletal muscle (De Angelis et al., 1999). Indeed, muscle SP cells express Sca-1, and importantly, Sca-1positive cells reside between muscle fibers prominently associated with blood vessels. By contrast, satellite cells on freshly isolated muscle fibers express CD34 but not Sca-1. In addition, Sca-1expressing cells lines isolated from muscle exhibit a high degree of plasticity (Torrente et al., 2001; Qu-Petersen et al., 2002; Tamaki et al., 2002). Together, these observations suggest that muscle-derived stem cells located as vascular-associated cells in skeletal muscle are a progenitor for satellite cells or muscle precursor cells. According to this hypothesis, muscle-derived stem cells and satellite cell populations would co-exist as distinct stem cell tiers in some state of equilibrium within adult muscle. Soon after initiation of muscle regeneration, the number of myogenic precursor cells thought to be derived from satellite cells are much greater than that of the resident satellite cells (Grounds et al., 1992). Therefore, one explanation for this apparent paradox is that muscle-derived stem cells give rise to the myogenic precursor cells. Additional experiments are required to deduce whether the flux between muscle-derived stem cells and satellite cell tiers is an ongoing process or is normally limited to a restricted period during development.
Muscle SP cells clearly possess the ability to form multiple hematopoietic colonies in vitro as well as hematopoietic differentiation in vivo after intravenous injection into irradiated mice (Gussoni et al., 1999). Recently, two groups demonstrated that CD45-positive cells within skeletal muscle contain HSC activity (Kawada and Ogawa, 2001; McKinney-Freeman et al., 2002). We also demonstrated that cells from muscle SP with in vitro hematopoietic potential are CD45-positive (CD45+ mSP). Bone marrow HSCs cannot be cultured under the conditions used in this work as reported previously (Traycoff et al., 1996). By contrast, muscle cells with hematopoietic potential are readily cultured in myoblast medium and have been suggested to maintain their hematopoietic potential for at least 5 d in vitro (Jackson et al., 1999). HSCs express several surface markers such as Sca-1 and c-kit (Goodell et al., 1997; Gussoni et al., 1999). Moreover, although freshly isolated muscle SP cells express Sca-1, they do not express c-kit (Gussoni et al., 1999). Furthermore, we failed to detect any muscle differentiation of bone marrow SP cells after co-culture with primary myoblasts. Therefore, marker expression and biological assays suggest some important differences between HSCs and muscle-derived cells with hematopoietic potential. In any case, these results strongly suggest that skeletal muscle is an adult organ containing a resident population of adult stem cells with hematopoietic potential. Recent bone marrow transplantation experiments have been interpreted to suggest that hematopoietic progenitors in muscle have a bone marrow origin (Kawada and Ogawa, 2001). However, a clear understanding of the identity and relationship between HSCs in bone marrow and hematopoietic potential cells within muscle remains to be elucidated. For example, it is interesting to speculate that muscle-derived hematopoietic potential cells represent the progenitors for hematopoietic cells such as macrophages and polymorphonuclear lymphocytes, which are mobilized in high numbers in regenerating muscle tissue (Seale and Rudnicki, 2000).
Direct proof that a single stem cell within the muscle SP fraction of cells is indeed capable to undergo hematopoietic, myogenic, or other differentiation remains lacking. It is entirely possible that the muscle SP fraction of cells contains multiple types of progenitors each with a restricted range of potential. It has been suggested recently that a single pluripotent HSC can give rise to many different cell types in a wide range of tissues in mice (Krause et al., 2001). Similar experiments using muscle SP cells should establish the potentiality of muscle-derived stem cells. Nevertheless, our data strongly support the existence of a tier of stem cells in addition to satellite cells in skeletal muscle with the potential to undergo myogenic specification.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
FACS®
Hoechst staining and FACS® analysis was performed as described previously (Jackson et al., 1999). In brief, hindlimb skeletal muscle was digested with collagenase type B and dispase II (Roche). About 2 x 107 cells were normally obtained from four adult mice (1- to 2-mo old). Bone marrow was prepared as described previously (Goodell et al., 1997). FACS® analysis was performed on a cell sorter (MoFlo®; Cytomation, Inc.) equipped with dual lasers. Hoechst staining was performed in DME supplemented with 2% FCS, 10 mM Hepes, 5 µg/ml Hoechst 33342 (Sigma-Aldrich), and with or without 50 µM verapamil (Sigma-Aldrich) at 37°C for 90 min. After Hoechst staining, immunostaining was performed by using antibodies reactive to Sca-1 or CD45 conjugated with phycoerythrin or FITC (PharMingen), respectively. Hoechst dye was excited at 351 nm by UV laser and its fluorescence was detected at two wavelengths using 424/44 (Hoechst blue) and 675/LP (Hoechst red) filters. FITC or phycoerythrin was excited at 488 nm by argon laser and its fluorescence was detected at FL1 (530/40) or FL2 (580/30) filter, respectively. Dead cells and debris were excluded from the plots based on propidium iodide staining (2 µg/ml; Sigma-Aldrich). Sorted cells were characterized by X-gal staining or immunohistochemistry on slide glass.
Cell culture
Single muscle fibers and dissociated muscle cells (muscle-derived cells) were isolated from hindlimb skeletal muscles prepared from 2-month-old heterozygous Myf5-nlacZ or MD6.0-lacZ transgenic mice by digestion in 0.4% collagenase type A (Roche) as described previously (Beauchamp et al., 2000). Isolated muscle fibers were immediately fixed or cultured in Methocult M3434 (StemCell Technologies Inc.). 5 x 103104 FACS® fractionated TgN(GFPU)5-Nagy (GFP), ROSA26-, or Myf5-nlacZmuscle SP cells were cultured or co-cultured with equal numbers of either primary myoblasts (Sabourin et al., 1999), C2C12 myoblasts, or C3H10T1/2 fibroblasts. Conditioned medium was obtained from growing primary myoblasts cultured for 4 d. Muscle SP cells were also purified from 2-week-old Pax7+/+ and Pax7-/- mice. pHAN-puro retrovirus vector was used as a control retrovirus vector, and retroviruses were prepared as previously described (Soneoka et al., 1995). pHAN-eGFP and pHAN-MyoD contain virus LTR and CMV promoterdriving enhanced GFP gene and MyoD gene, respectively. 1 x 104 FACS®-fractionated muscle SP cells were cultured in myoblast growth media on collagen-coated dishes for 24 h, followed by infection with retrovirus vectors for 3 h with polybrene. 24 h after retrovirus infection, cultures of muscle SP cells alone or together with equal numbers of primary myoblasts were performed. Cultures were maintained for 7 d in myoblast growth medium; Ham's F10 medium supplemented with 20% FCS, 2.5 ng/ml basic FGF (R&D Systems) on collagen-coated dishes, and DME supplemented with 5% horse serum was used for three additional days. Myogenic differentiation of muscle SP cells after co-culture with myoblasts was quantified by number of nuclei in desmin or MHC-positive muscle cells coexpressing ROSA26-lacZ or GFP per total input muscle SP cells expressing ROSA26-lacZ or GFP. At least 500 nuclei of input SP cells were counted for each experiment. At least three independent experiments were performed (n = 3).
Histochemistry
LacZ expression was detected by X-gal staining overnight as described previously (Asakura et al., 1995). Monoclonal anti-CD34, antiSca-1, or anti-CD45 (PharMingen) followed by FITC-conjugated antirat IgG secondary antibodies (CHEMICON International) were used for single muscle fibers as described previously (Beauchamp et al., 2000). Monoclonal anti-desmin (D33; Dako), anti-myosin heavy chain (MF20; Developmental Studies Hybridoma Bank), anti-Pax7 (Developmental Studies Hybridoma Bank), anti-MyoD (PharMingen), and VECTASTAIN® ABC kit (Vector Laboratories) or FITC-conjugated antimouse IgG antibodies (CHEMICON International) were used for immunohistochemistry. Double staining for 8-µm adult TA muscle sections was performed with monoclonal antiSca-1 (PharMingen), biotinylated antirat IgG, or antidystrophin (Sigma-Aldrich), and Texas redconjugated avidin (PharMingen) or FITC-conjugated avidin (Vector Laboratories), followed by antilaminin rabbit serum (Sigma-Aldrich) and FITC-conjugated anti-PECAM (PharMingen), FITC-conjugated antirabbit IgG (CHEMICON International), or rhodamine-conjugated antirabbit IgG (CHEMICON International).
Intramuscular injections
Muscle SP cells (36 x 104 cells) derived from Myf5-nlacZ or ROSA26 mice were injected into regenerating TA muscle of adult scid/bg immunodeficient mice (Ferrari et al., 1998). 24 h before cell injections, muscle regeneration was induced by injection of 25 µl of 10 µM cardiotoxin (Latoxan). 2 weeks or 1 month after injection of cells, TA muscles were stained with X-gal, and 8-µm frozen sections were prepared for immunohistochemistry. Myf5-nlacZexpressing nuclei were counted in serial sections adjacent to the lacZ-positive region. Myogenic differentiation of muscle SP cells by 2 weeks after transplantation was represented by total number of Myf5-nlacZpositive nuclei per each transplanted TA muscle. Three independent transplantation experiments were performed (n = 3). 1 month after injection of cells, TA muscles were also digested for culture experiments as described previously (Sabourin et al., 1999). Cultures were maintained for 4 d in myoblast growth medium on collagen-coated dishes.
Hematopoietic colony assays
Cells prepared from muscle, bone marrow, peripheral blood, and isolated muscle fibers were cultured in Methocult M3434 or M3630 (StemCell Technologies) for 1014 d. The number of colonies consisting of >50 cells were scored using an inverted microscope (Axiovert 25; Carl Zeiss MicroImaging, Inc.). Hematopoietic cells were identified by May-Grunwald's Giemsa (Sigma-Aldrich) and by immunohistochemistry with Mac1 and Gr1 antibodies (PharMingen) for detection of granulocyte/monocyte or B220 antibodies (PharMingen) for detection of pre-B cells followed by Vectastain ABC kit (Vector Laboratories).
![]() |
Footnotes |
---|
![]() |
Acknowledgments |
---|
This work was supported by grants to M.A. Rudnicki from the National Institutes of Health, the Canadian Institutes of Health Research, the Muscular Dystrophy Association, and the Canada Research Chair Program. A. Asakura is supported by a development grant from the Muscular Dystrophy Association. P. Seale holds a pre-doctoral fellowship from the Canadian Institutes of Health Research. M.A. Rudnicki holds the Canada Research Chair in molecular genetics and is an international scholar of the Howard Hughes Medical Institute.
Submitted: 20 February 2002
Revised: 30 July 2002
Accepted: 28 August 2002
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Asakura, A., M. Komaki, and M. Rudnicki. 2001. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation. 68:245253.[CrossRef][Medline]
Beauchamp, J.R., J.E. Morgan, C.N. Pagel, and T.A. Partridge. 1999. Dynamics of myoblast transplantation reveal a discrete minority of precursors with stem cell-like properties as the myogenic source. J. Cell Biol. 144:11131122.
Beauchamp, J.R., L. Heslop, D.S. Yu, S. Tajbakhsh, R.G. Kelly, A. Wernig, M.E. Buckingham, T.A. Partridge, and P.S. Zammit. 2000. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J. Cell Biol. 151:12211234.
De Angelis, L., L. Berghella, M. Coletta, L. Lattanzi, M. Zanchi, M.G. Cusella-De Angelis, C. Ponzetto, and G. Cossu. 1999. Skeletal myogenic progenitors originating from embryonic dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal muscle growth and regeneration. J. Cell Biol. 147:869878.
Ferrari, G., G. Cusella-De Angelis, M. Coletta, E. Paolucci, A. Stornaiuolo, G. Cossu, and F. Mavilio. 1998. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 279:15281530.
Fukada, S., Y. Miyagoe-Suzuki, H. Tsukihara, K. Yuasa, S. Higuchi, S. Ono, K. Tsujikawa, S. Takeda, and H. Yamamoto. 2002. Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent protein-gene transgenic mice. J. Cell Sci. 115:12851293.
Goodell, M.A., M. Rosenzweig, H. Kim, D.F. Marks, M. DeMaria, G. Paradis, S.A. Grupp, C.A. Sieff, R.C. Mulligan, and R.P. Johnson. 1997. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat. Med. 3:13371345.[Medline]
Gussoni, E., Y. Soneoka, C.D. Strickland, E.A. Buzney, M.K. Khan, A.F. Flint, L.M. Kunkel, and R.C. Mulligan. 1999. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 401:390394.[CrossRef][Medline]
Heslop, L., J.E. Morgan, and T.A. Partridge. 2000. Evidence for a myogenic stem cell that is exhausted in dystrophic muscle. J. Cell Sci. 113:22992308.
Jackson, K.A., T. Mi, and M.A. Goodell. 1999. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc. Natl. Acad. Sci. USA. 96:1448214486.
Jackson, K.A., S.M. Majka, H. Wang, J. Pocius, C.J. Hartley, M.W. Majesky, M.L. Entman, L.H. Michael, K.K. Hirschi, and M.A. Goodell. 2001. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107:13951402.
Kawada, H., and M. Ogawa. 2001. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle. Blood. 98:20082013.
Lagasse, E., H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse, L. Osborne, X. Wang, M. Finegold, I.L. Weissman, and M. Grompe. 2000. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 6:12291234.[CrossRef][Medline]
McKinney-Freeman, S.L., K.A. Jackson, F.D. Camargo, G. Ferrari, F. Mavilio, and M.A. Goodell. 2002. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl. Acad. Sci. USA. 99:13411346.
Pittenger, M.F., A.M. Mackay, S.C. Beck, R.K. Jaiswal, R. Douglas, J.D. Mosca, M.A. Moorman, D.W. Simonetti, S. Craig, and D.R. Marshak. 1999. Multilineage potential of adult human mesenchymal stem cells. Science. 284:143147.
Qu-Petersen, Z., B. Deasy, R. Jankowski, M. Ikezawa, J. Cummins, R. Pruchnic, J. Mytinger, B. Cao, C. Gates, A. Wernig, and J. Huard. 2002. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J. Cell Biol. 157:851864.
Sabourin, L.A., A. Girgis-Gabardo, P. Seale, A. Asakura, and M.A. Rudnicki. 1999. Reduced differentiation potential of primary MyoD-/- myogenic cells derived from adult skeletal muscle. J. Cell Biol. 144:631643.
Seale, P., L.A. Sabourin, A. Girgis-Gabardo, A. Mansouri, P. Gruss, and M.A. Rudnicki. 2000. Pax7 is required for the specification of myogenic satellite cells. Cell. 102:777786.[Medline]
Soneoka, Y., P.M. Cannon, E.E. Ramsdale, J.C. Griffiths, G. Romano, S.M. Kingsman, and A.J. Kingsman. 1995. A transient three-plasmid expression system for the production of high titer retroviral vectors. Nucleic Acids Res. 23:628633.[Abstract]
Tamaki, T., A. Akatsula, K. Ando, Y. Nakamura, H. Matsuzawa, T. Hotta, R.R. Roy, V.R. Edgerton. 2002. Identification of myogenic-endothelial progenitor cells in the intersitial spaces of skeletal muscle. J. Cell Biol. 157:571577.
Torrente, Y., J.P. Tremblay, F. Pisati, M. Belicchi, B. Rossi, M. Sironi, F. Fortunato, M. El Fahime, M.G. D'Angelo, N.J. Caron, et al. 2001. Intraarterial injection of muscle-derived CD34+Sca-1+ stem cells restores dystrophin in mdx mice. J. Cell Biol. 152:335348.
Weintraub, H., R. Davis, S. Tapscott, M. Thayer, M. Krause, R. Benezra, T.K. Blackwell, D. Turner, R. Rupp, S. Hollenberg, et al. 1991. The myoD gene family: nodal point during specification of the muscle cell lineage. Science. 251:761766.[Medline]
Zambrowicz, B.P., A. Imamoto, S. Fiering, L.A. Herzenberg, W.G. Kerr, and P. Soriano. 1997. Disruption of overlapping transcripts in the ROSA ß geo 26 gene trap strain leads to widespread expression of ß-galactosidase in mouse embryos and hematopoietic cells. Proc. Natl. Acad. Sci. USA. 94:37893794.