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© The Rockefeller University Press,
0021-9525/2003/8/511 $5.00
The Journal of Cell Biology, Volume 162, Number 3, 511-520
Article |
Identification of a putative pathway for the muscle homing of stem cells in a muscular dystrophy model
Address correspondence to Yvan Torrente, Department of Neurological Sciences, University of Milan, Padiglione Ponti, Ospedale Policlinico, via Francesco Sforza 35, 20122 Milan, Italy. Tel.: 39-02-55033874. Fax: 39-02-50320430. email: torrenteyvan{at}hotmail.com
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Abstract |
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Attempts to repair muscle damage in Duchenne muscular dystrophy (DMD) by transplanting skeletal myoblasts directly into muscles are faced with the problem of the limited migration of these cells in the muscles. The delivery of myogenic stem cells to the sites of muscle lesions via the systemic circulation is a potential alternative approach to treat this disease. Muscle-derived stem cells (MDSCs) were obtained by a MACS® multisort method. Clones of MDSCs, which were Sca-1+/CD34-/L-selectin+, were found to adhere firmly to the endothelium of mdx dystrophic muscles after i.v. or i.m. injections. The subpopulation of Sca-1+/CD34- MDSCs expressing L-selectin was called homing MDSCs (HMDSCs). Treatment of HMDSCs with antibodies against L-selectin prevented adhesion to the muscle endothelium. Importantly, we found that vascular endothelium from striate muscle of young mdx mice expresses mucosal addressin cell adhesion molecule-1 (MAdCAM-1), a ligand for L-selectin. Our results showed for the first time that the expression of the adhesion molecule L-selectin is important for muscle homing of MDSCs. This discovery will aid in the improvement of a potential therapy for muscular dystrophy based on the systemic delivery of MDSCs.
Key Words: gene therapy; muscle derived stem cell; transplantation; muscle homing; dystrophin
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Introduction |
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Populations of pluripotent stem cells were obtained from muscles using different procedures. A side population (SP) was initially obtained from muscles by FACS® on the basis of Hoechst dye exclusion (Gussoni et al., 1999; Jackson et al., 1999). Muscle-derived stem cells (MDSCs) were also obtained by a series of preplatings and shown to express Sca-1 and CD34 (Lee et al., 2000; Deasy et al., 2001; Torrente et al., 2001). These MDSCs have the capacity to differentiate into all major blood lineages in vitro (Torrente et al., 2001). Moreover, bone marrow restoration was observed after injection of muscle SP cells (a stem cell population obtained by FACS®) into the tail vein of lethally irradiated mice (Jackson et al., 1999). Of particular significance is the observation that transplanted SP cells isolated from bone marrow or muscle also actively participated in myogenic regeneration. MDSCs and satellite cells are distinct cell populations, as demonstrated by the normal numbers of MDSCs and the complete absence of satellite cells in Pax7 (gene specifically expressed in myoblasts derived from satellite cells) mutant muscles (Seale et al., 2000).
However, the relationship between MDSCs and the mechanisms underlying the muscle regeneration are still poorly understood: do they remain as a quiescent pool or do they contribute to form skeletal muscle fibers after extensive tissue degeneration? Systemic transplantation of bone marrow–derived stem cells or even of MDSCs had a very limited impact on muscle cell replacement and did not improve murine muscular dystrophy (Ferrari et al., 2001; Torrente et al., 2001). This might be explained by poor recruitment of bone marrow–derived stem cells and MDSCs to the dystrophic muscle. An understanding of the nature of the factors responsible for stem cell homing to muscles will be invaluable in attempts to improve systemic delivery of stem cells for muscle diseases.
In this context, our attention was focused on the expression of adhesion molecules involved in muscle homing by MDSCs. MACS® multisort columns were used to enrich Sca-1+/CD34- MDSCs. We identified a clonable subset of MDSCs expressing L-selectin, an adhesion molecule critical for transendothelial migration of the blood- and bone marrow–derived cells. This subset of MDSCs will be referred to as homing MDSCs (HMDSCs). Using intravital microscopy, we showed that these HMDSCs adhered firmly to the endothelium of mdx muscle microvessels after i.v. or i.m. injections. Treatment of HMDSCs with an antibody against L-selectin prevented their adhesion to the blood vessels. Intravenous injections of HMDSCs, obtained from transgenic newborn mice carrying a LacZ reporter gene under the desmin promoter, produced ß-galactosidase (ß-gal)– and dystrophin-positive fibers in many muscles. The discovery of the mechanism involved in the muscle homing of MDSCs will aid in the improvement of a potential therapy for muscular dystrophy based on the systemic delivery of such stem cells.
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Results |
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Adhesion of one subpopulation of MDSCs to muscle microcirculation
MDSCs (obtained by a series of six preplatings) contain cells capable of adhesion to muscle blood vessels, migration, engraftment, and myogenic differentiation after intravascular injection in mice (Torrente et al., 2001). Flow cytometric analysis for Sca-1 and CD34 of MDSCs showed different subpopulations. One subpopulation comprising 69% of the MDSCs was positive for both Sca-1 and CD34. A second subpopulation containing 24% of the MDSCs was Sca-1 positive but CD34 negative, and a third subpopulation was only positive for CD34 (7%) (Fig. 1 a).
To identify which cells within the MDSCs were capable of muscle homing, the MDSCs were separated into subpopulations (i.e., Sca-1-/CD34+, Sca-1+/CD34+, and Sca-1+/CD34-) by immunomagnetic selection (MACS® multisort). We then tested the adhesion to muscle blood vessels of these three subpopulations of MDSCs. Boluses of 5 x 105 fluorescently labeled cells were injected into the tail vein or into the quadriceps muscle, and their adhesion to the pectoral muscle vessels was recorded. After i.v. or i.m. injections, no vascular interaction was observed for the Sca-1-CD34+ subpopulation. A few Sca-1+/CD34+ cells interacted with muscle capillaries after i.v. injection but not after i.m. injection. The Sca-1+/CD34- cells were clearly distinguishable from the other two MDSC subpopulations by their significant migration within injected quadriceps after single injection (Fig. 2, c and d). The ß-gal staining of muscles injected with Sca-1+/CD34- MDSCs derived from ROSA26 mice confirmed the presence of donor cells spread within myofibers and near muscle capillaries and arterioles (Fig. 2, e–g). Moreover, after i.m. injections, these cells were able to migrate from the injected muscle tissue to the blood stream and then adhered to the endothelial lining of several distant muscles (Fig. 2, h–m).
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To verify whether L-selectin was involved in the adhesion of MDSCs to blood vessels, we treated Sca-1+/CD34- MDSCs with antibodies to L-selectin before their i.v. injection. This treatment reduced >70% of the adhesion of these cells to the muscle blood vessels. This demonstrated that L-selectin is involved in the migration of MDSCs to the muscles. Adhesion fractions of injected MDSCs were determined by counting the number of interacting cells in each muscle vessel per number of cells that passed through the same vessel during an injection. The subpopulation of MDSCs (Sca-1+/CD34-/L-selectin+) capable of adhesion to muscle blood vessels represents <3% of all MDSCs and will thus be referred to as homing MDSCs (HMDSCs). To increase the percentage of HMDSCs, we cloned the Sca-1+/CD34- MDSCs obtained from newborn Des-LacZ mice. Among the 30 clones produced, two (named G13 and F9) expressed the L-selectin on all cells and CD44 adhesion markers on 30% of these cells (unpublished data). The morphology of these cells was similar to medium-sized blast cells. In a myogenic differentiation medium, G13 and F9 clones lost the L-selectin expression (Fig. 3 a), indicating a specific correlation between the loss of this adhesion molecule and the lineage commitment of these stem cells. These clones produced cells expressing either myosin heavy chain (MyHC) (markers of late myogenic differentiation) or desmin and m-cadherin (markers of quiescent muscle satellite cells), indicating two characteristics of the myogenic potential of the HMDSCs (Fig. 3, d–g). These data were confirmed by immunoblot analysis. Multinucleated MyHC-positive myotubes were also observed after a 14-d culture of Sca-1+/CD34-/L-selectin- MDSC clones. These results indicate that L-selectin expression in the Sca-1+/CD34- MDSC subpopulation does not correlate with the capacity to differentiate into muscle cells. Metalloproteinases are a family of molecules that are critical in cell migration and remodeling of the ECM. We observed that HMDSCs expressed higher levels of MMP-2 and MMP-9 than myoblasts obtained after HMDSC commitment (Fig. 3 h). These data support the notion that the high migratory capacity of HMDSCs is the result of a combination of factors.
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2% of fibers of a cross section of the pectoralis muscle were not only dystrophin positive but also contained ß-gal–positive nuclei (Fig. 4 e). In the other muscles, the percentage of dystrophin-positive muscle fibers with ß-gal nuclei was much lower (0.5–1.0% of total fibers in a given cross section) (Fig. 4 g). The dystrophin antibody did not cross-react with autosomal dystrophin-related proteins, such as utrophin. Control mdx muscles contained rare revertant fibers that were dystrophin positive (Hoffman et al., 1990) but ß-gal negative. |
Discussion |
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Using the intravital microscopy method, we identified a subpopulation of Sca-1+/CD34- MDSCs that are responsible for the migration to the mesodermal derivatives (muscle and bone marrow) after their i.m. transplantation sharing the same properties and phenotype (Sca-1+, CD34-, and lineage marker negative) as the so-called SP. We found that only 30% of the Sca-1+/CD34- MDSCs express the L-selectin adhesion molecule. Clones of these stem cells resulted in a corresponding enrichment in the transplantable muscle content of this subset. Moreover, these clones expressed a high level of MMP-2 and MMP-9, two matrix-degrading metalloproteinases that play an important role in tissue remodeling and in processes involved in cell migration (Birkedal-Hansen et al., 1993).
Sca-1+/CD34-/L-selectin+ MDSCs (HMDSCs) did not "home" specifically to the muscle tissues. We found, however, a few of them in spleen, liver, lung, and brain after i.v. injection. Thus muscle homing was probably related to a high expression of the L-selectin ligands on the vessels of inflamed muscles, as is the case for dystrophic muscles (Berenson et al., 1988). Importantly, we found that endothelium from dystrophic muscle expresses MAdCAM-1, but not E- and P-selectin. MAdCAM-1 is a ligand for L-selectin that expressed selectively at venular sites of lymphocyte extravasation into mucosal lymphoid tissues and lamina propria, where it directs local lymphocyte trafficking (Berg et al., 1993; Briskin et al., 1993). It has been previously shown that MAdCAM-1 is also expressed on chronically inflamed endothelium from nonlymphoid organs and mediates the recruitment of leukocytes into sites of inflammation (Yang et al., 1997; Connor et al., 1999; Hillan et al., 1999; Souza et al., 1999; Kanwar et al., 2000). Our results represent the first demonstration that vascular endothelium from dystrophic muscle is able to express MAdCAM-1. Interestingly, we show that only blood vessels from young mdx mice express MAdCAM-1, whereas older mice down-regulate the mucosal addressin from their surface.
Although antibody against L-selectin reduced muscle homing of HMDSCs, some attachment of HMDSCs to the muscle tissues was still observed after this blockade. The remaining homing capacity could be attributed either to an incomplete blocking of all L-selectin molecules on the HMDSCs or to the rapid expression of new L-selectin sites on these cells. However, an alternative hypothesis is that other cell adhesion molecules may be involved in the in vivo muscle homing of HMDSCs. Collectively, these findings showed that muscle homing may result from a mixture of pathways including tissue-specific interactions between L-selectin adhesion molecules of stem cells and ligands present on the endothelium layer of blood vessels after local damage.
The absence of L-selectin antigen after the commitment of HMDSCs indicates a possible functional role in the maintenance of a "primitive" state of multipotent stem cells that coincides with their homing properties. In this regard, it is interesting that L-selectin is also expressed in the earliest hematopoietic stem/progenitor cells (HSPCs) and in intermediate stages of leukocyte development, and all erythroid and megakaryocytic lineage cells are devoid of L-selectin expression (Kansas et al., 1990; Terstappen et al., 1992; Sackstein, 1997). Moreover, several studies have indicated L-selectin as a "bone marrow homing molecule" (Mazo et al., 1998; Greenberg et al., 2000), suggesting a role for L-selectin adhesive interactions with its ligand in the creation and/or perpetuation of HSPC microenvironmental niches after hematopoietic stem cell transplantation (Dercksen et al., 1995; Watanabe et al., 1998; Koenig et al., 1999). In agreement with these data, we observed a reconstitution of the hematopoietic compartment of lethally irradiated mdx/mdx recipients after injection of HMDSCs.
The Sca-1+/CD34-/L-selectin+ cells differentiate well in vitro in myogenic lineage and can rescue the dystrophic phenotype after their i.v. injection into mdx/mdx mice. However, the muscle dystrophin restoration was below the levels needed to provide clinical benefits in DMD and not in correspondence with the high attachment to muscle blood vessels observed 2 h after i.v. injection of HMDSCs. It is possible that these cells are in competition with the resident stem cells for muscle fiber repair. In the case of bone marrow transplantation, the damage is usually whole body irradiation or other myeloablative agents (Hendrikx et al., 1996). Both approaches probably kill bone marrow stem cells and result in a free stem cell niche where the injected bone marrow stem cells can home (Jackson et al., 1999; Wright et al., 2002) and have no competition. The presence of only a few HMDSCs in the bone marrow of mdx/mdx mice not irradiated and the total reconstitution obtained after irradiation agree with this interpretation. Additionally, muscle incorporation of the HMDSCs initially attached to the muscle blood vessels may prevalently generate satellite cells (as indicated by in vitro differentiation experiments), which did not fuse with existing muscle fibers in the time course of this experiment.
The HMDSCs attached initially to the muscle blood vessels may remain as a multipotent circulating pool of cells (Delassus and Cumano, 1996; Shi et al., 1998) and eventually migrate to other tissues during their life span. The progressive muscle degeneration and vessel wall calcification present in the dystrophic muscles may significantly reduce the migration of HMDSCs in the damaged muscle tissue (unpublished data). In the future, stem cell transplantation could be optimized by performing them during the initial stage of DMD disease to provide levels of muscle engraftment that would be clinically useful. Our results show an important observation that will help to start the investigation of the mechanism of muscle homing, and this may eventually aid in improving the efficacy of the systemic delivery of stem cells to repair dystrophic muscles.
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Materials and methods |
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Isolation of MDSCs
Muscle-derived cells were isolated using a previously described protocol (Rando and Blau, 1994; Torrente et al., 2001) and preplated in noncoated flasks with Ham's F10 supplemented with 20 µg/ml pancreatic insulin, 50 ng/ml stem cell factor, 15% FBS, and 1% penicillin/streptomycin. All the culture medium supplies were purchased from GIBCO BRL. Sca-1+ cells were purified by positive selection by using the Sca-1 multisort kit (Miltenyi Biotec). After the isolation of Sca-1+ cells, multisort microbeads were removed using the MACS® multisort release reagent, and the Sca-1+ cells were incubated with a biotinated, conjugated CD34 antibody (1/50) and resuspended with an antibiotin conjugated with paramagnetic microbeads (Miltenyi Biotec). After selection, aliquots of the Sca-1+/CD34+, Sca-1+/CD34-, Sca-1-/CD34+ cell fractions were analyzed to assess purity. For two-color flow cytometry, FITC–anti-CD34 (BD Biosciences) and phycoerythrin-conjugated anti–Sca-1 Mab (Miltenyi Biotec) were used as previously described (Forni, 1979; Gehling et al., 1997; Lange et al., 1999; Nakamura et al., 1999). Flow cytometric analysis was performed on a FACScan® flow cytometer using Cell Quest software (Becton Dickinson) with 10,000 events recorded for each sample.
Clonogenic and differentiation potential of Sca-1+/CD34- MDSCs
For clonal analysis, the Sca-1+/CD34- isolated cells were resuspended in uncoated wells of 96-well plates (1 cell/well) and cultured with the proliferating medium as above. Only the wells containing a single cell were used. The ability of Sca-1+/CD34- MDSCs to undergo differentiation into myogenic lineage was tested with Ham's F10 supplemented with 5% FBS, and after 14 d of culture, differentiated myoblasts were detected by immunostaining with antibodies against desmin (1:100; Sigma-Aldrich), MyHC (1:200; Ylem), and m-cadherin (1:50; Santa Cruz Biotechnology, Inc.). For Western blot analyses, 100 µg of extracted proteins was separated on 6% polyacrylamide gels and electrotransferred onto nitrocellulose membranes (Bio-Rad Laboratories) and incubated with monoclonal antibodies directed against either dystrophin, utrophin, or m-cadherin and revealed using a commercially available chemiluminescence kit (Ultra ECL; Pierce Chemical Co.). Metalloproteinase activity was assessed using 10% gelatin zymogram gels, as described previously (El Fahime et al., 2000).
Intramuscular transplantation of MDSCs into mdx
5 x 105 MDSCs prepared from newborn male F1 Balb/c(H2d)-C57BL10J(H2b) mice and Sca1+/CD34- MDSCs from newborn male Des-LacZ mice (H2b) were injected into the right TA of three groups each of five female 2-mo-old C57BL/10ScSn mdx/mdx (H2b) mice. Mice were anesthetized with an i.p. injection of physiologic saline (10 ml/kg) containing ketamine (5 mg/ml) and xylazine (1 mg/ml). Detection of chromosome Y was performed as previously described (Caron et al., 1999). To verify tolerance induction after transplantation, we examined Balb/c skin grafts placed on C57BL/10ScSn mdx/mdx mice. Skin from the tails of Balb/c donors was engrafted to the backs of three C57BL/10ScSn mdx/mdx recipients (Rosenberg, 1991). The grafts were examined daily for evidence of edema, hair growth, and rejection.
Intravital microscopy
Muscle homing and vascular adhesion properties were also verified into the pectoral muscle of three groups of mdx/mdx mice (n = 15) injected into the TA muscles with 5 x 105 of each subpopulation of MDSCs (i.e., Sca-1-/CD34+, Sca-1+/CD34+, and Sca-1+/CD34-) as previously described (Torrente et al., 2001). An intravital microscope (Olympus BX50WI) equipped with water immersion objectives (Olympus Achroplan; focal distance 3.3 mm, NA 0.5) was used for these experiments. The MDSCs were fluorescently labeled with 2',7'-bis-(carboxyethyl)-5(and-6) carboxy-fluorescein (BCECF; Molecular Probes). All scenes were recorded on videotape using a silicon-intensified target video camera (VE 1000-SIT; Dage MTI), a time and frame counter (ELCA), and a high picture quality SVHS Panasonic VCR.
Intravenous transplantation of MDSCs into lethally irradiated mdx mice
The Sca-1+/CD34- MDSCs and bone marrow cells were obtained from Balb/c newborn mice (H-2d haplotype) and injected intravenously into lethally irradiated (950 cGy) C57BL/10ScSn mdx/mdx (H-2b haplotype). Animals were then followed for 8 wk. No changes in general health status were noted in recipient mice. 20 C57BL/10ScSn mdx/mdx mice received 5 x 107 bone marrow–derived cells. 20 C57BL/10ScSn mdx/mdx mice received both the Sca-1+/CD34- MDSCs (50 x 104) and bone marrow–derived cells (5 x 106). Two groups served as controls. Five C57BL/10ScSn mdx/mdx mice received pooled bone marrow cells from Balb/c mice after irradiation (control 1). Four C57BL/10ScSn mdx/mdx mice were irradiated and did not receive cell transplantation to determine whether the irradiation dose chosen was lethal (control 2). All four of these mice died within 2 wk. For transplantation into secondary recipients, bone marrow was harvested from a rescued mdx/mdx mouse, and 8 x 105 mononucleated cells were injected into each of five mdx/mdx recipients, prepared as described above.
In vivo histochemistry and immunocytochemistry
For histochemistry on tissue sections, samples were frozen in liquid nitrogen–cooled isopentane and cryostat sectioned. Slides were examined by light microscopy for ß-gal–positive myofibers (Li et al., 1993). Detection of dystrophin was performed with a polyclonal antibody against the COOH 60-kD Dys fragment (gift of J.S. Chamberlain, University of Michigan, Ann Arbor, MI). Antibodies were visualized using an HRP-coupled secondary antibody (Bio-Rad Laboratories). The Lac-Z, dystrophin double-positive myofibers were counterstained with hematoxylin and eosin. A fluorescence microscope (Leica DMIR2) equipped with Leica Qfluoro software was used for these experiments.
Characterization of muscle homing by [3H]glycerol labeling and autoradiography
5 x 105 HMDSCs were incubated overnight at 37°C in RPMI supplemented with 10 µCi/ml [3H]glycerol (Dupont), as previously described (Constantin et al., 1997), and injected intravenously into mdx/mdx mice. Animals were killed 2 h later, muscle, lung, kidney, liver, and blood tissues were collected, and radioactive content was measured in a ß-counter (LS1801; Beckman Coulter). We compared the distribution of radioactivity of five 2-mo-old mdx/mdx mice injected i.v. with 10 x 105 HMDSCs with five dystrophic animals injected with HMDSCs pretreated for 15 min at room temperature with 100 µg/µl anti–L-selectin MEL-14 (gift from E.C. Butcher, Stanford University, Stanford, CA). To assure a longer blocking of the L-selectin on HMDSCs, L-selectin pretreatment was accompanied by i.v. injection of anti–L-selectin (400 µg/ml of antibody diluted in 500 µl of sterile HBSS). To exclude the potential effects of the complement, the F(ab')2 fragment of anti–L-selectin was generated using the immunoPure F(ab')2 preparation kit (Pierce Chemical Co.) as previously described (Lamoyi, 1986). In this experiment, five mdx/mdx animals were injected with HMDSCs pretreated for 15 min at room temperature with 100 µg/µl of F(ab')2 anti–L-selectin. For histologic localization of radiolabeled cells, 8-µm frozen sections of muscle tissues were placed on Histostick-coated slides (Accurate Chemicals), fixed with methanol, and washed with PBS. The slides then were dipped in Kodak NTB 2 emulsion (Eastman Kodak Co.) and exposed for 6 wk at 4°C. The slides were developed and fixed using EDF/EDP Photochemicals (Eastman Kodak Co.) according to the processing protocol from the manufacturer.
In vivo staining of endothelial adhesion molecules
MAbs anti–E-selectin, –P-selectin, and –MAdCAM-1 and an isotype-matched control antibody (anti–human Ras) were labeled using the Alexa Fluor®488 labeling kit (Molecular Probes). 50 µg fluorescent mAb was injected intravenously. 20 min later, the animal was anesthetized and perfused through the left ventricle with cold PBS (Piccio et al., 2002). Striate muscle vessels were visualized using the intravital microscopy setting as described for intravital microscopy experiments. Anti–L-selectin mAb Mel-14 was from American Type Culture Collection. Anti–E-selectin and –P-selectin antibodies (RME-1 and RMP-1) were obtained as previously described (Walter et al., 1997a, b). Anti–MAdCAM-1 was provided by E.C. Butcher. Green CMFDA (5-chloromethylfluorescein diacetate) for the labeling of HMDSCs for intravital microscopy was prepared as a stock solution in DMSO and kept at -20°C until the moment of use.
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Acknowledgments |
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This work has been supported by the Association Française Contre les Myopathies, the Muscular Dystrophy Association, the Canadian Institute for Health Research, the Canadian Muscular Dystrophy Association, the Stem Cell Network, the Italian Ministry of Health, and the Centro Dino Ferrari (Department of Neurological Science, University of Milan).
Submitted: 1 October 2002
Accepted: 9 June 2003
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References |
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