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Expression of Functional CXCR4 by Muscle Satellite Cells and Secretion of SDF-1 by Muscle-Derived Fibroblasts is Associated with the Presence of Both Muscle Progenitors in Bone Marrow and Hematopoietic Stem/Progenitor Cells in Muscles

^a Stem Cell Biology Program at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA;
^b Department of Transplantology, Polish-American Children’s Hospital at Jagiellonian University, Cracow, Poland

Key Words. Stem cell plasticity • CXCR4 • SDF-1 • Muscle satellite cells • Hematopoietic stem/progenitor cells

Correspondence: Mariusz Z. Ratajczak M.D., Ph.D., Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA. Telephone: 502-852-1788; Fax: 502-852-3032; e-mail: mzrata01{at}louisville.edu

	ABSTRACT

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We found that the murine cell lines C2C12 and G7 derived from muscle satellite cells, which are essential for muscle regeneration, express the functional CXCR4 receptor on their surface and that the specific ligand for this receptor, -chemokine stromal-derived factor 1 (SDF-1), is secreted in muscle tissue. These cell lines responded to SDF-1 stimulation by chemotaxis, phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 and AKT serine-threonine kinase, and calcium flux, confirming the functionality of the CXCR4 receptor. Moreover, supernatants derived from muscle fibroblasts chemoattracted both satellite cells and human CD34⁺ hematopoietic stem/progenitor cells. In a similar set of experiments, supernatants from bone marrow fibroblasts were found to chemoattract CXCR4⁺ satellite cells just as they chemoattract CD34⁺ cells. Moreover, preincubation of both muscle satellite cells and hematopoietic stem/progenitor CD34⁺ cells before chemotaxis with T140, a specific CXCR4 inhibitor, resulted in a significantly lower chemotaxis to media conditioned by either muscle- or bone marrow-derived fibroblasts. Based on these observations, we postulate that the SDF-1-CXCR4 axis is involved in chemoattracting circulating CXCR4⁺ muscle stem/progenitor and circulating CXCR4⁺ hematopoietic CD34⁺ cells to both muscle and bone marrow tissues. Thus, it appears that tissue-specific stem cells circulating in peripheral blood could compete for SDF-1⁺ niches, and this would explain, without invoking the concept of stem cell plasticity, why hematopoietic colonies can be cultured from muscles and early muscle progenitors can be cultured from bone marrow.

	INTRODUCTION

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The concept of transdifferentiation of adult tissue-specific stem cells recently has been called into question [1, 2]. Studies aimed at reproducing transdifferentiation experiments with neural stem cells have failed [3]. Similarly, it has been shown that hematopoietic stem/progenitor cells present in muscle tissue are in fact of bone marrow origin [4–6]. Recent studies on chimeric animals by transplantation of a single hematopoietic stem cell (HSC) marked with a green fluorescent protein into lethally irradiated nontransgenic mice demonstrated that transdifferentiation of circulating HSCs and/or their progeny is an extremely rare event, if it occurs at all [7]. Thus, the phenomena supporting the concept of plasticity of adult stem cells may have been artifacts resulting from the fact that these experiments were not performed at the single-cell level, and the investigators were dealing with mixed populations of various stem cells that could be present in different organs/tissues [1, 2]. To explain why hematopoietic stem/progenitor cells were found in muscle tissue [8] and, vice versa, why muscle stem/progenitor cells were found in suspensions of bone marrow-derived cells [9, 10], we hypothesized in this work that: A) muscle progenitors, like hematopoietic CD34⁺ cells, display the CXCR4 receptor on their surface; B) the corresponding chemoattractant, stromal-derived factor 1 (SDF-1), is expressed by muscle tissues as well as by the bone marrow, and C) the CXCR4-SDF-1 axis plays an important role in the homing of these cells to muscles as well as to bone marrow. We further hypothesized that CXCR4⁺ muscle satellite cells and hematopoietic stem/progenitor cells that circulate in the body may compete for occupancy of SDF-1⁺ niches, and it is this competition, rather than stem cell plasticity, that explains why hematopoietic progenitors are found in muscles and why muscle satellite cells can be isolated from cultures of bone marrow cells [1–10].

	MATERIALS AND METHODS

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Expression of SDF-1 in Muscle Tissue
Heart muscle fragments obtained during cardiac operations (children aged 2 weeks to 3 months undergoing surgery for congenital cardiovascular malformations) and striated muscles obtained from diagnostic biopsies performed on children with muscular dystrophy were snap-frozen. The study was approved by the Institutional Review Board committee at Collegium Medicum Jagiellonian University, Cracow. The samples of muscle tissue were subsequently processed to obtain a single-cell suspension and to grow fibroblasts. Briefly, small biopsies of muscle were carefully dissected, and the muscle tissue was thoroughly minced and then digested by adding 1 mg/ml collagenase type I and letting it stand for 1 hour at 37°C. The tissue was triturated vigorously, and the cells were collected by centrifugation. The cells were then cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 100 IU/ml penicillin, 10 µg/ml streptomycin, and 50 µg/ml neomycin in the presence of 10% heat-inactivated fetal bovine serum (FBS) in a humidified atmosphere with 5% CO₂ at 37°C. The media were changed every 48 hours. Expressions of SDF-1 and kit ligand (KL) in human muscle-cell-derived fibroblasts were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) as described previously [11–13].

Expression and Functional Analysis of CXCR4
Murine satellite C2C12 and G7 cells were obtained from American Type Culture Collection (ATCC; Rockville, MD; http://www.atcc.org). These cells were cultured in DMEM supplemented with 100 IU/ml penicillin, 10 µg/ml streptomycin, and 50 µg/ml neomycin in the presence of 10% FBS and, in order to induce myotube formation and differentiation, cells were exposed to high-glucose media according to the ATCC protocol. Expression of CXCR4 in these cells lines was evaluated by RT-PCR. Primer sequences for murine CXCR4 were forward primer: 5'-CCC GAT AGC CTG TGG ATG GTG GTG T-3' and reverse primer: 5'-AGC TTT TGA ACT TGG CCC CGA GGA A-3'. The responses of these cells to SDF-1 were evaluated using phosphorylation of intracellular pathway proteins, calcium flux, and chemotaxis assays. Briefly, cells were kept in RPMI medium containing low levels of bovine serum albumin (BSA) (0.5%) to render the cells quiescent and then stimulated with SDF-1ß (100–300 ng/ml) or hepatocyte growth factor (HGF, 10 ng/ml) for 2–10 minutes. The extracted proteins were separated on a 12% SDS-PAGE gel and transferred onto a nitrocellulose membrane (Schleicher & Schuell; Keene, NH; http://www.schleicher-schuell.com), as previously described [11–13]. Phosphorylation of the intracellular kinases mitogen-activated protein kinase (MAPK) p44/42 (Thr 202/Tyr 204) and AKT was detected using commercial mouse phospho-specific monoclonal antibody (mAb) for MAPK p44/42 and rabbit phospho-specific polyclonal antibodies for AKT (all from Cell Signaling, New England Biolabs; Beverly, MA; http://www.net.com), with horseradish peroxidase-conjugated goat anti-mouse IgG or goat anti-rabbit IgG as secondary antibodies (Cell Signaling, New England Biolabs). Equal loading in the lanes was evaluated by stripping the blots and reprobing with appropriate mAbs: p42/44 anti-MAPK antibody clone #9102 and anti-AKT antibody clone #9272 (Santa Cruz Biotechnology; Santa Cruz, CA; htttp://www.scbt.com). The membranes were developed with an ECL reagent (Amersham Biosciences; Little Chalfont, UK), dried, and subsequently exposed to film (HyperFilm; Amersham). For calcium flux studies, cells were incubated for 30 minutes at 30°C with 1–2 µM Fura-2/AM (Molecular Probes; Eugene, OR; http://www.probes.com). After incubation, cells were washed once, resuspended in loading buffer, and analyzed within 1 hour. For directional chemotaxis studies, murine satellite C2C12, G7, or hematopoietic Sca-1⁺ cells or human bone marrow-derived CD34⁺ cells were made quiescent, as described above, and the directional movement of cells toward the gradient of SDF-1 concentration across an 8-µm (satellite cells) or 5-µm (Sca-1⁺ and CD34⁺ cells) pore polycarbonate membrane was evaluated, as described previously [11–13]. The lower chamber was filled either with SDF-1 at a concentration of 100 ng/ml or with conditioned media derived from human or murine bone marrow- or muscle-tissue-derived fibroblasts. A 0.5% BSA RPMI medium was used as a negative control. The inserts were removed from the transwells after 48 hours (for satellite cells) or 3 hours (for Sca-1⁺ and CD34⁺ cells), and the cells remaining in the upper chambers were scraped off with cotton wool. The cells that had transmigrated were counted, either on the lower side of the membrane (satellite cells) or on the bottom of the transwells (hematopoietic cells), as described previously [12]. Some of the directional migration experiments were performed using cells preincubated (for 30 minutes at 37°C) in the presence of 1 µM T140-truncated polyphemusin [14] analogue (a gift of Dr. Nobutaka Fuji, Kyoto University, Japan) or with anti-CXCR4 (10 µg/ml). In the chemotaxis experiments, supernatants conditioned by bone marrow stroma cells were pretreated with anti-SDF-1 (100 µg/ml) (R&D Systems, Inc.; Minneapolis, MN; http://www.rndsystems.com), as previously described [12].

Detection of mRNA for Early Muscle Markers in Peripheral Blood Mononuclear Cells
Mononuclear cells were isolated from peripheral blood obtained from three normal participants and three patients, mobilized by G-CSF. RT-PCR for early muscle markers was performed using the following primers: for MyoD, the forward primer was 5'-CGG CGG CGG AAC TGC TAC GAA-3' and the reverse primer was 5'-GGG GCG GGG GCG GAA ACT T-3'; and for myogenin, the forward primer was 5'-AGC GCC CCC TCG TGT ATG-3' and the reverse primer was 5'-TGT CCC CGG CAA CTT CAG C-3'. Primer sequences were evaluated for their specificity at the National Center for Biotechnology Information, Bethesda, MD.

	STATISTICAL ANALYSES

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All results are presented as mean ± standard error. Statistical analyses of the data were performed using the Student’s t-test, with p < 0.05 considered significant.

	RESULTS AND DISCUSSION

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Evidence is accumulating that HSCs are present in muscle tissues [4–6, 8, 15] and, vice versa, that muscle stem/progenitor cells may be found in bone marrow [9, 16, 17]. To explain this phenomenon, the notion of stem cell plasticity has been invoked, but, recently, the concept has been the subject of much controversy [1, 2].

We reported recently that human rhabdomyosarcoma cells highly expressed the receptor CXCR4 on their surface [12]. Since rhabdomyosarcomas may originate from very primitive muscle cells, we asked whether CXCR4 was expressed by muscle stem/progenitor cells as well. To address this question, we selected two murine satellite cell lines, G7 and C2C12, and, by employing RT-PCR and Western blotting, we found that CXCR4 was expressed on those cells (Fig. 1). Next, to determine whether CXCR4 was functional on those cells, we stimulated them with SDF-1 (Fig. 2) and found that they responded to SDF-1 stimulation with chemotaxis, phosphorylation of MAPK p42/44 and AKT, and calcium flux. Since the c-met receptor is a marker of muscle satellite cells [18], we employed its specific ligand, HGF, as a positive control.

View larger version (47K): [in this window] [in a new window]   Figure 1. CXCR4 is expressed by murine muscle satellite cell lines. A) RT-PCR detection of expression of mRNA for CXCR4 in murine muscle satellite cell lines. Lane 1 shows ß-actin expression, lanes 2 and 3 show expressions of mRNA for CXCR4 (364 bp) in lysates derived from G7 and C2C12 cells, respectively; lane 4 is a negative control (H20 instead of mRNA). B) Phosphorylation of MAPK p42/44 in nondifferentiated murine satellite C2C12 cells (left) and C2C12 cells forced to differentiate into myotubes (right) stimulated by SDF-1ß (100 or 300 ng/ml) for 2 or 10 minutes. Lane 1 shows quiescent cells (-); lanes 2 and 3 show cells stimulated for 2 and 10 minutes by SDF 100 ng/ml; lanes 4 and 5 show cells stimulated by SDF-1 (300 ng/ml) for 2 and 10 minutes, respectively. The experiment was repeated three times with similar results. Representative Western blots are shown.

View larger version (24K): [in this window] [in a new window]   Figure 2. CXCR4 is functional on murine muscle satellite cells. A) Chemotaxis of murine satellite C2C12 (left) and G7 cells (right) to SDF-1 (100 ng/ml) or HGF (10 ng/ml). The data are shown as a percentage of chemotaxis to medium alone (-). Data from three independent experiments done in quadruplicate are pooled together. * indicates p < 0.001 as compared to chemotaxis to medium alone. B) Phosphorylation of MAPK p42/44 and serine-threonine kinase AKT in murine satellite C2C12 (left) and G7 cells (right) stimulated by SDF-1ß (100 ng/ml). (-) represents quiescent cells and SDF2' and SDF10' represent cells stimulated by SDF-1 for 2 and 10 minutes, respectively. The experiment was repeated three times for C2C12 and twice for G7 cells with similar results. Representative Western blots are shown. C) Calcium flux in G7 cells stimulated by SDF-1 (100 ng/ml). The experiment was repeated three times and a representative result is shown.

Thus, our data provide new evidence that the CXCR4-SDF-1 axis could be involved in muscle development by regulating the biology of muscle progenitor/satellite cells. Supporting this is a report that mouse embryos with CXCR4 and SDF-1 knockouts displayed defects in heart muscle formation [19, 20]. We suggest additional studies be done to see whether other muscle-related defects are present in these animals.

Next, because SDF-1 is secreted by bone marrow-derived fibroblasts [17, 18], we further hypothesized that circulating hematopoietic stem/progenitor cells both in humans and mice could be chemoattracted to muscle tissue in a CXCR4-SDF-1-dependent manner. As human and murine SDF-1 show species cross-reactivity, we studied the chemoattraction of human CD34⁺ bone marrow-derived cells to conditioned media harvested from ex vivo-expanded human muscle-derived fibroblasts (Fig. 3). We found that conditioned media harvested from human heart- and skeletal muscle-derived fibroblasts chemoattracted CD34⁺ cells (Figs. 3A and 3B, respectively). Recombinant SDF-1 or conditioned media harvested from bone marrow fibroblasts were employed as positive controls (Fig. 3A). Moreover, when those cells were preincubated with T140 [14] before chemotaxis, or the conditioned media were precleared with anti-SDF-1 antibodies, less chemoattraction was observed (Fig. 3). However, since there was still some chemotaxis observed, other chemoattractants not yet identified could be involved. On the basis of these experiments, we postulate that the chemoattraction of CD34⁺ cells by muscle tissue-derived fibroblasts provides a molecular explanation for why circulating hematopoietic stem/progenitor cells can be detected in muscle tissue [4–6, 9, 15]. Moreover, since muscle-derived fibroblasts in addition to SDF-1 (Fig. 4) may secrete other hematopoietic factors, such as, for example, KL (Fig. 4B), these cells find a supportive environment that protects them from undergoing apoptosis.

View larger version (18K): [in this window] [in a new window]   Figure 3. Chemotaxis of human bone marrow-derived CD34+ cells. A) Chemotaxis of bone marrow-derived CD34+ cells to SDF-1 or to conditioned media (CM) derived from bone marrow (BM) or heart stroma cells. Data from three independent experiments done in quadruplicate are pooled together. In some of the experiments, cells were pretreated before chemotaxis with T140, a CXCR4 inhibitor. * indicated p < 0.00001 as compared with non-T140-pretreated cells. B) Chemotaxis of bone marrow-derived CD34+ cells to medium alone (control) or to skeletal muscle (SM) stroma CM. In some of the experiments, cells were pretreated before chemotaxis with T140, a CXCR4 inhibitor, or SM stroma CM was precleared with antibodies against SDF-1. Data from two independent experiments done in quadruplicate are pooled together. * indicates p < 0.00001 as compared with cells that were chemoattracted by SM stroma CM alone.

View larger version (82K): [in this window] [in a new window]   Figure 4. SDF-1 is expressed in muscle-derived fibroblasts. A) Normal human skeletal muscle fibroblasts expanded from muscle tissue (magnification = 320x). B) RT-PCR detection of expression of mRNA for SDF-1 in human muscle tissue. Lanes 1 and 3 show expression of mRNA for SDF-1 (281 bp) and KL (359 bp), respectively, in skeletal muscle-derived fibroblasts; lanes 2 and 4 are negative controls (H20 instead of mRNA). The experiment was repeated three times, and a representative result is shown.

View larger version (38K): [in this window] [in a new window]   Figure 5. Chemotaxis of murine muscle satellite cells. A) Chemotaxis of murine C2C12 cells to medium alone (a) and to medium conditioned by human bone marrow-derived stroma (b and c). c) shows murine satellite cells that were pretreated before chemotaxis with T140 (a CXCR4 inhibitor). The satellite cells present on the lower side of the transwell membrane were stained with hematoxylin-eosin. A representative result is shown. B) Chemotaxis of satellite cells shown as percentages of control. The left bar shows chemotaxis to normal culture medium, not conditioned by bone marrow stroma fibroblasts, used as a control (-) (100%). The middle bar shows chemotaxis to medium conditioned by bone marrow-derived fibroblasts (BM stroma CM). The right bar shows chemotaxis to BM stroma CM by cells pretreated with T140. The experiment was repeated three times, and a representative result is shown. * indicates p < 0.00001 as compared with the control or T140 or anti-SDF-1 pretreated cells. C) Chemotaxis of murine C2C12 cells (open bars) and G7 cells (closed bars) to medium alone (control) and to conditioned medium derived from skeletal muscle (SM) stroma (SM stroma CM) in the absence (first and second pair of bars) or presence of T140 or anti-SDF-1 antibodies (third and fourth pair of bars, respectively). * indicates p < 0.00001 as compared with cells that were chemoattracted by medium alone, SM stroma CM in the presence of T140, or SM stroma CM precleared with anti-SDF-1.

It has long been recognized that peripheral blood is a "highway" for lymphoid memory cells and hematolymphopoietic stem cells circulating in the body [21]. Recent data have also demonstrated the presence in the peripheral blood of other stem cells that are able to give rise to cells of neural or muscle tissues [9, 22]. Based on these observations, we hypothesized that, in addition to hematolymphopoietic stem cells, other tissue-specific stem cells may also use this route to maintain a balanced pool of tissue-specific stem cells. This would be especially important for the stem cells of tissues that are located in anatomic locations dispersed throughout the body. Thus, hematopoietic and muscle stem cells need to circulate to maintain a balanced pool of stem cells between distant areas of bone marrow and muscles; likewise, neuroectodermal stem cells may also circulate to maintain a stem cell pool in the adrenal medulla and the sympathetic nervous system. Supporting this latter idea is the fact that SDF-1 is also secreted by neural tissue, and CXCR4 is expressed on the surface of early neural cells [23, 24]. Hence, a similar mechanism to the one described here for muscle satellite cells may explain why neural progenitors are detectable in hematopoietic tissues [22] and why HSCs are found in the brain [25]. Since we recently found that CXCR4 is expressed by murine embryonic stem cells (unpublished), it seems likely that the SDF-1-CXCR4 axis could play a more universal role in regulating trafficking of tissue-specific stem cells [26]. In support of this, CXCR4 was recently described as playing an important role in the migration of primordial germ cells [27]. Our preliminary data (Fig. 6) suggest that circulating early muscle tissue-specific precursor cells that express MyoD are present in peripheral blood during mobilization.

View larger version (60K): [in this window] [in a new window]   Figure 6. A) Expression of mRNA for early muscle stem/progenitor cells in normal nonmobilized peripheral blood mononuclear cells. Lane 1: marker; lane 2: ß-actin; lane 3: MyoD; lane 4: myogenin; lane 5: negative control of RT-PCR reaction. B) Expression of mRNA for early stem/progenitor cells in peripheral blood mononuclear cells derived from G-CSF-mobilized patients. Lane 1: marker; lane 2: ß-actin; lane 3: MyoD; lane 4: myogenin; lane 5: negative control of RT-PCR reaction (H20 instead of mRNA). The experiment was performed on mononuclear cells mobilized from three normal donors as well as three patients, with similar results. A representative RT-PCR is shown.

View larger version (35K): [in this window] [in a new window]   Figure 7. Diagram of the hypothesis postulating the competition of circulating CXCR4+ cells for occupancy of SDF-1+ niches. We hypothesize that CXCR4 is expressed on hematopoietic stem/progenitor cells, muscle satellite/progenitor cells, and other tissue-specific progenitor cells that circulate at low levels in the peripheral blood to maintain a balanced stem cell pool in distant parts of the body. The number of these cells in the peripheral blood increases during tissue damage or mobilization. The identity of the chemoattractants released from the damaged tissues requires further study. We do not exclude the involvement of other tissue-specific chemoattractants and the possibility that circulating stem/progenitor cells have a higher affinity for stem cell niches in the organs from which they are derived. There is a high probability that a similar mechanism operates for CXCR4+ neural stem/progenitor cells and hepatic oval cells as well.

	ACKNOWLEDGMENT

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This work was supported by an NIH grant R01 HL61796-01 and KBN grant PBZ-501/Z/B/1/2002 to M.Z.R.. The authors are indebted to Drs. M. Mierzynski and J. Kolcz from the Jagiellonian University, Cracow, Poland for their help and critical comments. M.M. and M.K. equally contributed to this work.

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