1 Robarts Research Institute, Krembil Centre for Stem Cell Biology and Regenerative Medicine, 100 Perth Drive, London, Ontario, N6A 5K8, Canada
2 The University of Western Ontario, Department of Microbiology and Immunology, Toronto, Ontario, Canada
3 University of Toronto, Department of Bioengineering, Toronto, Ontario, Canada
* Author for correspondence (e-mail: mbhatia{at}robarts.ca)
Accepted 21 June 2005
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Summary |
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Key words: Hematopoietic stem cells, Bone marrow, Skeletal muscle, Migration
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Introduction |
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In the current study, skeletal muscle and BM-derived CD45+ cells were functionally compared to examine the mechanisms that regulate the seeding of BM-derived cells in the skeletal muscle compartment. Transplantation of BM-derived cells into conditioned recipients fully replaced the skeletal-muscle CD45+ compartment. However, these muscle CD45+ cells contained a higher percentage of cells co-expressing Sca-1, reduced capacity for B-lymphoid differentiation, and were deficient in their ability to expand in response to MS-5-BM-derived stroma as compared to CD45+ cells in the BM. In transwell assays, C2C12-derived myotubes were capable of inducing the migration of BM-derived HPCs, and were distinct from HPCs migrating to BM-derived stromal cells as revealed by primary and secondary migration potential. Furthermore, BM CD45+ cells migrating to skeletal muscle cells were shown to require the hepatocyte growth factor (HGF)/c-met axis and migrated to skeletal muscle independently of the SDF-1/CXCR4 axis. Our study reveals that the BM compartment includes a unique subset of CD45+ HGF/c-met responsive cells capable of migrating to skeletal muscle, thereby providing a basis for the regulatory network that governs tracking of CD45+ BM cells to skeletal muscle versus BM microenvironments.
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Materials and Methods |
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Mononuclear cell isolation
Whole BM was flushed from the femur and tibia of GFP or NOD/SCID mice. Tibalis anterior, quadriceps and calf muscles were removed and minced in Iscove's Modified Dulbecco's Medium (IMDM) (Gibco Life Sciences, Burlington, ON). BM and muscle were treated with 340 U/ml of collagenase type II for 1 hour, triturated with an 18-gauge needle, and filtered through 70 µm and 40 µm mesh to remove debris. Cells were washed with PBS-5%FBS (Gibco Life Sciences). In some experiments MNCs were further purified by Percoll centrifugation (McKinney-Freeman et al., 2002).
Flow-cytometry and cell sorting
BM and skeletal muscle cells were washed and resuspended in PBS-5%FBS (10x106 cells/ml). Individually isolated hematopoietic colonies were stained in 200 µl PBS-5%FBS. Cells were stained with monoclonal antibody (mAb) against CD45, conjugated to either allophycocyanin (APC) (30-F11), or phycoerythrin (PE) in combination with mAbs that target traditionally used hematopoietic-lineage-specific cell-surface markers for: granulocytes/neutrophils via Gr-1-APC (RB6-8C5), T cells via CD3-PE (17A2), B cells via B220 (CD45R)-PE (RA3-6B2), erythroid cells via Ter119-PE (TER-119), macrophages via CD11b-PE (M1/70), or primitive blood cells via Sca-1-PE (E13-161.7) (BD Pharmingen, Mississauga, ON). For the purification of CD45+ cells, skeletal muscle cells and BM-derived MNCs were treated with NH4Cl buffer (Stem Cell Technologies) for 5 minutes at 4°C to remove red blood cells, before staining with CD45-APC. Cells were stained for 30 minutes at 4°C, washed twice and stained for 10 minutes at 4°C with 7-Aminoactinomycin D (7-AAD) (BD Pharmingen) to differentiate between viable and non-viable cells. Surface-receptor expression was examined on a FACSCaliburTM. Alternatively, viable GFP+CD45+ or GFP+Sca-1+CD45+ cells were sorted using a FACSVantageTM.
In vitro progenitor cell assays
For detection of erythroid and myeloid progenitor cells, whole skeletal muscle and BM or FACS sorted CD45+ or Sca-1+CD45+ cells were plated in methylcellulose medium containing 15% FBS, 1% BSA, 10-4 M 2-mercaptoethanol, 10 µg/ml recombinant human (rh) insulin, 200 µg/ml human transferrin, 2 mM L-glutamine, 50 ng/ml recombinant murine (rm) stem cell factor, 10 ng/ml rm-IL-3, 3U/ml rh-Erythropoietin, 10 ng/ml rh-IL-6 (GF M3434, Stem Cell Technologies, Vancouver, BC). For detection of B-cell progenitors methylcellulose media was supplemented with 30% FBS, 10-4 M 2-mercaptoethanol, 2 mM L-glutamine and 10 ng/ml rh-IL-7 (M3630, Stem Cell Technologies).
Stromal/CD45+ cell co-cultures
MS-5 stromal cells (kind donation of Kiri Mori, University of Tokyo, Japan) were propagated in IMDM-8%FBS (Itoh et al., 1989). For co-culture experiments, MS-5 cells were grown to confluence in 6-well tissue culture plates (Gibco Life Sciences) and cultured for an additional week before the seeding of skeletal muscle cells and BM-derived CD45+ cells. MS-5 cells were cultured in the absence of CD45+ cells as controls. In addition, CD45+ cells were grown in IMDM-8%FBS alone. Cells were cultured for periods of 2, 3, 4 and 5 weeks. At the end of each culture period 1/10 of the cells were used to determine the total number of CD45+ cells by flow-cytometry and the remaining cells were plated in colony-forming-unit (CFU) assays.
Cell-migration assays
Transwell migration assays were completed as described previously (Jo et al., 2000; Kim and Broxmeyer, 1998
). Confluent layers of MS-5 stromal cells, C2C12 myotubes or primary myogenic cells derived from skeletal muscle of wild-type CD-1 adult mice (Yaffe, 1968
) were cultured in 600 µl of IMDM-8%FBS (MS-5) or DMEM-5% horse serum (HS) (C2C12) on the lower chamber of 24-well transwell assay dishes (Corning Life Sciences, Acton, MA). Random migration controls consisted of IMDM-8%FBS or DMEM-5%HS alone in the lower chamber. Whole BM cells (500,000 per well for primary assays, 100,000 to 500,000 per well for secondary assays) from FVB GFP mice were placed in the upper chamber in a 100 µl total volume of the appropriate media. Upper and lower transwell chambers were separated by a 5 µm pore polycarbonate membrane. Migration of CD45+ cells and CFUs from the upper to the lower chamber was measured by flow-cytometry and progenitor cell assays after 24 hours at 37°C and 5% CO2. For SDF-1 neutralization assays, SDF-1 antibody (79014.111) (R&D Systems, Hornby, ON) was added to lower chambers at 60 µg/ml 24 hours before and immediately before the loading of BM cells into the upper chamber. The binding of SDF-1 to CXCR4 was blocked by treatment of BM cells with 20 µg/ml anti-rat-CXCR4 (Torrey Pines Biolabs) for 40 minutes at 4°C before seeding into the upper chamber. To examine the role of c-met, HGF and basic FGF (bFGF) in BM-cell migration, BM CD45+ cells were treated with murine c-met-blocking antibody (R&D) for 40 minutes at 4°C. Antibody-treated or -untreated cells were then loaded into the upper chamber of transwells containing MS-5, C2C12 or 40 ng/ml of either HGF or bFGF (R&D) in the lower chamber.
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Results |
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In the mouse, BM-derived HPCs are enriched within a population of cells expressing the Ly antigen Sca-1 (Spangrude et al., 1988). We therefore examined and compared the frequency of Sca-1+ cells in the muscle CD45+ fraction of BM-transplanted and non-transplanted mice, and in the BM of donor-GFP mice. Since Sca is expressed by other cell types, the combination of Sca expression and expression of CD45 together on the same cells is required to define lineage origin of Sca-expressing cell types in any given tissue. Replacement of muscle CD45+ cells by donor BM also had no effect on the frequency of Sca-1+ cells within this hematopoietic (CD45+) fraction (Fig. 1C). However, the skeletal-muscle-derived CD45+ fraction contained a 15-fold higher percentage of Sca-1+ cells compared with donor GFP BM cells (Fig. 1C, P
0.05). Analysis of Sca-1 expression in BM-transplanted and non-transplanted mice demonstrates that skeletal muscle-derived CD45+ cells are unique to BM cells, because the Sca-1-expressing subfraction in the BM environment is not altered following replacement of the CD45+ fraction with transplanted BM-derived cells. Analysis of additional markers, such as c-kit and CD34 did not demonstrate any differences in expression when comparing BM with skeletal-muscle-derived CD45 cells (data not shown). Since the number of cells collected for these analyses was identical in all four independent experiments (a total of 2500 live events, Fig. 1C), and total number of muscle cells is considerably higher in the skeletal muscle than BM cellularity in the mouse, it is likely that Sca-1+ cells have a tendency of migrating to skeletal muscle. To further elucidate the relationship between muscle and marrow-hematopoietic cells, BM-derived Sca-1+CD45+ cells were i.v. transplanted into sub-lethally irradiated mice at doses allowing a wide range of hematopoietic chimerism in muscle and marrow sites. Linear-regression analysis determined that the level of chimerism arising in the muscle is directly related to the level of chimerism detected in the BM (Fig. 1D; r2=0.968). Our data provide evidence that skeletal muscle CD45+ cells repopulating the muscle of recipient mice after BM transplantation are solely derived from transplanted BM of the donor.
Skeletal-muscle- and BM-derived CD45+ cells are distinct
As our preliminary Sca-1 analysis suggested potential distinctions in the differentiative program of CD45+ cells in the muscle and marrow environments, we directly compared the erythroid, myeloid and B-lymphoid capacity of BM and muscle CD45+ cells using methylcellulose hematopoietic progenitor assays. Whole skeletal muscle and BM were treated with collagenase in the identical manner to isolate CD45+ cells by FACS. Equal numbers of cells, derived from the skeletal muscle or BM, were plated in myeloid-progenitor- or pre-B-progenitor-detection assays. The progenitor capacity of FACS-isolated CD45- cells was also examined; however, similarly to other studies (Asakura et al., 2002; Kawada and Ogawa, 2001a
; Kawada and Ogawa, 2001b
; McKinney-Freeman et al., 2002
; Polesskaya et al., 2003
), no hematopoietic progenitors were detected in this fraction (data not shown). Interestingly, progenitors were detected at an equivalent frequency within muscle and BM CD45+ subfractions [39±9 (muscle) and 37±8 (BM) per 10,000 cells], and no differences were detected in their erythroid and myeloid progenitor composition (Fig. 2Ai,ii). B-cell progenitor analysis determined that skeletal muscle-derived CD45+ cells contained a twofold lower frequency of B-cell progenitors in comparison to the marrow (Fig. 2Aiii). Thus, the frequency of CFU within muscle and BM CD45+ cells does not correlate with the differences in the proportion of Sca-1+ cells identified within these sites. Our results demonstrate that skeletal muscle and BM-derived CD45+ cells have equivalent erythroid and myeloid potential, but distinct B-lymphoid differentiation capacities.
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The stroma induced expansion of muscle and BM-derived CFU progenitors was examined using methylcellulose assays. After 2 weeks in culture the mean fold-expansion of skeletal muscle-derived hematopoietic progenitors was 3.5-fold lower than that detected from BM CD45+ cells seeded cultures [Fig. 2Biv, 7.1±0.4 (BM) versus 1.7±0.7 (muscle); P0.05]. Differences in the number of muscle- and BM-derived progenitors were even greater after 5 weeks of stromal co-culture; BM-CD45+-seeded cultures demonstrated a 5.5-fold greater level of progenitor cell expansion [Fig. 2Biv, 65.9±1.7 (BM) versus 12.2±8.2 (muscle); P
0.05]. We suggest that skeletal-muscle-derived CD45+ or CD45+Sca+ cells possess a markedly reduced capacity for expansion on stromal cells compared with cells derived from BM suggesting that, although skeletal-muscle-derived CD45+ cells originate from the BM, these subsets are functionally distinct from those found in the BM.
BM-derived CD45+ cells migrate in response to mature skeletal muscle cells
Following i.v. transplantation into conditioned recipients, reconstituting cells migrate directly to the BM in response to chemoattractive factors (Kollet et al., 2001; Orschell-Traycoff et al., 2000
). However, it remains unclear whether similar mechanisms are responsible for seeding the skeletal muscle site. The small number of cells involved in the homing and seeding process (Orschell-Traycoff et al., 2000
), together with the competing influences of stem cell niches in other organs and tissues (Bjornson et al., 1999
; Gussoni et al., 1999
; Lagasse et al., 2000
), complicate the study of cell-trafficking to the muscle in vivo. Accordingly, we used transwell assays as a surrogate system to examine the migration of BM CD45+ cells towards a muscle environment. For this purpose, confluent layers of C2C12 myotubes or primary myogenic cells derived from skeletal muscle of CD-1 mice, were grown on the lower chamber of transwell dishes. BM MNCs from GFP mice were placed in the upper chamber and the percentage of GFP+CD45+ cells and functional hematopoietic progenitors migrating to lower chambers was analyzed after 24 hours. Medium only, used to culture both C2C12 and primary myogenic cells, was placed in the lower chamber of selected wells as a comparative control for non-specific cell migration. To provide a quantitative measure of migration efficiency in this system, the migration of BM cells towards MS-5 stromal cells was examined. MS-5 cells secrete SDF-1, a known chemoattractant of hematopoietic progenitors (Aiuti et al., 1997
). As expected, a significant proportion of BM-derived CD45+ cells (42±4%) and progenitors (14±2%) migrated to MS-5 stromal cells compared with culture media only (Fig. 3; P
0.05). Interestingly, mature skeletal muscle cells were also capable of mediating the migration of BM-derived CD45+ cells (18±2%), including a population of progenitors amounting to 6±0.4% of input progenitors (Fig. 3; P
0.05). Use of these transwell migration systems demonstrates that mature myogenic (C2C12 or primary) cells produce a chemoattractant(s) capable of inducing migration of BM-derived CD45+ cells and HPCs.
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CD45+ cells migrating in response to myogenic cells and stroma represent distinct populations of BM cells
Since BM-derived CD45+ cells and progenitors migrating towards mature muscle cells represented a smaller population of cells compared with those migrating towards stroma (Fig. 3), we hypothesized that CD45+ cells migrating to muscle might either be included in the population of cells with stroma-cell-migrating potential, or might represent a distinct population. To functionally define the relationship of BM CD45+ cells migrating to muscle or stroma, a secondary transwell migration protocol was designed. As illustrated in Fig. 4A, BM CD45+ cells were allowed to migrate to mature myotubes over a 24-hour period. Cells were isolated from the lower chamber (1° migrating cells) and upper chamber (1° non-migrating cells), and a portion of each population was used to determine progenitor content. The remaining cells were re-challenged in secondary transwell migration assays containing either C2C12 myotubes (red) or MS-5 stromal cells (blue) in the lower chamber. In secondary assays 38±6% of 1° migrating CD45+ cells, and 9±5% of functional progenitors, maintained myofiber-migrating capacity (Fig. 4Bi, red). Thus, the muscle migratory potential of 1° migrating cells is diminished upon re-challenge in secondary assays, but remained significant by comparison with media controls (Fig. 4Bi, red versus white; P0.05). However, 1° migrating CD45+ cells and progenitors failed to migrate towards MS-5 stromal cells in secondary assays (Fig. 4Bi, blue versus gray). These data demonstrate that BM-derived cells that migrate to mature myotubes do not respond to chemoattractants produced by BM stroma.
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Myofiber-induced migration of BM CD45+ cells depends on HGF and c-met (HGF/c-met axis), but not SDF-1 and CXCR4 (SDF-1/CXCR4 axis)
SDF-1 is a highly efficacious chemoattractant of hematopoietic progenitors (Aiuti et al., 1997), and the only chemokine shown to mediate the migration of BM reconstituting cells (Wright et al., 2002
). SDF-1-induced chemotaxis is mediated through its only known receptor, CXCR4 (Oberlin et al., 1996
). Thus, SDF-1 and CXCR4 are strong candidates in regulating the migration of BM-derived CD45+. To investigate the role of SDF-1 and CXCR4 in the migration of CD45+ cells and HPCs towards muscle, transwell migration assays were used in combination with SDF-1 neutralizing antibodies (Lataillade et al., 2000
), or CXCR4 blocking (Petit et al., 2002
). As a positive control, the effect of CXCR4 and SDF-1 antibodies on MS-5 stroma cell mediated migration was also examined. The addition of anti-SDF-1 to transwell dishes containing MS-5 stromal cells (black), or the treatment of BM MNCs with anti-CXCR4 (hatched), reduced the proportion of migrating CD45+ cells and progenitors by 1.5-fold and twofold, respectively, compared with stroma-cell-migration alone (white) (Fig. 5Ai; P
0.05). These data verify that SDF-1 and CXCR4 regulate progenitor-cell migration to BM stroma, and validates ligand-neutralizing or receptor-blocking-antibody treatment as reliable methods of testing potential chemoattractants in transwell systems. Surprisingly however, in transwell systems that contain confluent layers of mature C2C12-derived myotubes in the lower chamber, the percentage of migrating CD45+ cells and progenitors was not altered by SDF-1-neutralizing or CXCR4-blocking antibodies (Fig. 5Aii). Treatment of stroma-cell and myofiber monolayers with anti-SDF-1, or of BM cells with anti-CXCR4, demonstrates that myofiber-induced migration of BM-derived HPCs occurs independently of SDF-1 and CXCR4, further emphasizing that stroma and progenitor cells that migrate to muscle cells represent distinct populations of BM CD45+ cells.
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In-vitro migration assays provide an excellent system to evaluate potential mechanisms of cellular migration. However, to more directly evaluate migration of BM cells to the skeletal muscle versus those engrafting the recipient BM, donor GFP+ BM cells were transplanted into recipient mice. The expression of cell surface c-met on donor (GFP+)-hematopoietic (CD45+) cells was then compared between skeletal muscle and BM sites. Cell-surface c-met expression on donor CD45-hematopoietic cells engrafting the skeletal muscle was significantly higher (60.4±12.5%) than on cells engrafting the BM site (2.1±0.8%), thereby further supporting the specific role of the HGF/c-met axis in the migration of BM cells to the skeletal muscle niche (Fig. 5E).
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Discussion |
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The presence of CD45+ cells in the muscle has been well documented (Dell'Agnola et al., 2002; Geiger et al., 2002
; Gussoni et al., 1999
; Jackson et al., 1999
; Jay et al., 2002
; Kawada and Ogawa, 2001a
; Seale et al., 2000
). Thus far, only indirect comparisons of BM and muscle CD45+ cells have been made. By comparing identically treated BM and muscle CD45+ cells, our study demonstrates that the CD45+ cells residing in these two compartments are functionally distinct. The most compelling evidence supporting this conclusion is the reduced expansion of muscle-derived CD45+ cells in response to BM-stromal microenvironments. Because MS-5 stromal cells were selected based on their capacity to produce both secreted and membrane-bound growth factors that promote the proliferation and differentiation of CD45+ hematopoietic cells (Nishi et al., 1996
; Suzuki et al., 1992
), the intrinsic differences between skeletal muscle and BM-derived CD45+ cells suggests that these two fractions have different cell physiology. In addition, a large proportion of skeletal-muscle-derived CD45+ cells might lack hematopoietic potential, because CD45+ cells that coexpress Sca-1 did not possess concomitant progenitor function. This would be consistent with recent findings that demonstrate that skeletal-muscle-derived CD45+ cells might be more responsive to myogenic factors (Asakura et al., 2002
; LaBarge and Blau, 2002
; Polesskaya et al., 2003
), and might promote skeletal-muscle repair (Polesskaya et al., 2003
; Sherwood et al., 2004
), thereby suggesting that the formation of hematopoietic tissue is not the primary function of CD45+ cells residing in the skeletal muscle.
Transwell migration has been used in several studies to examine the chemotactic properties of specific molecules, and has been proven to be a reliable indicator of the mechanisms that govern cellular trafficking in vivo (Aiuti et al., 1997; Bleul et al., 1996
; Jo et al., 2000
; Peled et al., 1999
; Petit et al., 2002
; Poznansky et al., 2000
). Our study demonstrates for the first time that mature muscle cells can induce the transwell-migration of BM-derived CD45+ cells. The inability of progenitors that migrate to muscle cells to migrate towards MS-5 stromal cells instead, where the major chemoattractant is SDF-1 (Aiuti et al., 1997
), implies that BM cells that are destined to reside in the skeletal muscle do not respond to SDF-1. Loss of SDF-1 responsiveness has been associated with decreased progenitor-cell-retention in the BM (Aiuti et al., 1997
; Levesque et al., 2003
; Ma et al., 1999
; Petit et al., 2002
; Shen et al., 2001
). Decreased responsiveness of CD45+ to SDF-1, which results in decreased BM retention, might play a role in the migration of c-met+ cells to the muscle site in response to HGF. Recent observations suggest that, BM cells seed in the skeletal muscle and progress along a differentiation pathway, which involves the formation of satellite cells in response to muscle-damage and/or -fusion, to form functional myofibers (LaBarge and Blau, 2002
). Irrespective of the cellular mechanism, our study suggests that c-met and HGF are involved in the migration of these BM-derived cells to skeletal muscle, and therefore represents the initial phase mediating subsequent skeletal muscle repair.
Taken together, we suggest the existence of a discrete population of CD45+ cells in the BM, which lacks chemotactic responsiveness to BM stroma but functions to migrate to mature muscle. Considering the myogenic nature of BM-derived CD45+ cells seeding the muscle (Asakura et al., 2002; Ferrari et al., 1998
; Gussoni et al., 1999
; LaBarge and Blau, 2002
; McKinney-Freeman et al., 2002
; Polesskaya et al., 2003
), augmentation of SDF-1- and HGF-responsiveness might provide a useful means of treating muscle-degeneration and -damage by recruiting CD45+ BM cells to the damaged skeletal muscle without cellular transplantation. The immune-deficient nature of the recipient mice used in this study might influence muscle- and BM-derived CD45+ compartments, and it is therefore important to corroborate our observations and interpretations by using in-vitro assay systems that are not influenced by these in-vivo based parameters. This is of great importance regarding future studies, related to muscle damage to elucidate the potential function and basis for CD45+ tracking in vivo, and is probably influenced by inflammatory responses that are dampened in the immune-deficient setting. Our study expands the current model of hematopoiesis and includes the existence of distinct pools of CD45+ cells in the BM that, in response to specific signals, are responsible for hematopoiesis in the marrow or in seeding alternate tissue sites (such as skeletal muscle). This previously unappreciated basis for cellular tracking now helps to define regulatory networks that distinguish the stem cell niche of the BM from skeletal muscle microenvironments.
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Acknowledgments |
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