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The Journal of Immunology, 2005, 175: 1399-1405.
Copyright © 2005 by The American Association of Immunologists

The Colony-Stimulating Factor 1 Receptor Is Expressed on Dendritic Cells during Differentiation and Regulates Their Expansion1

Kelli P. A. MacDonald2,*, Vanessa Rowe*, Helen M. Bofinger*, Ranjeny Thomas{dagger}, Tedjo Sasmono{ddagger}, David A. Hume{ddagger} and Geoffrey R. Hill*

* Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Queensland, Australia; {dagger} Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Woolloongabba Queensland, Australia; and {ddagger} Cooperative Research Centre for Chronic Inflammatory Diseases and Australian Research Council Special Research Centre for Functional Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
The lineage of dendritic cells (DC), and in particular their relationship to monocytes and macrophages, remains obscure. Furthermore, the requirement for the macrophage growth factor CSF-1 during DC homeostasis is unclear. Using a transgenic mouse in which the promoter for the CSF-1R (c-fms) directs the expression of enhanced GFP in cells of the myeloid lineage, we determined that although the c-fms promoter is inactive in DC precursors, it is up-regulated in all DC subsets during differentiation. Furthermore, plasmacytoid DC and all CD11chigh DC subsets are reduced by 50–70% in CSF-1-deficient osteopetrotic mice, confirming that CSF-1 signaling is required for the optimal differentiation of DC in vivo. These data provide additional evidence that the majority of tissue DC is of myeloid origin during steady state and supports a close relationship between DC and macrophage biology in vivo.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Dendritic cells (DC)3 represent a heterogeneous population of APCs, which include CD11c+CD4+, CD11c+CD8+, CD11c+CD4–CD8–, and CD11cdimB220+ subsets in the mouse. The relationship between the various DC subsets and cell lineage remains highly controversial. Although it is clear that they can be differentiated from both monocytes and granulocyte myeloid precursors (1), well-constructed studies also indicate that some DC may derive from common lymphoid precursors (2, 3). The expression of the c-fms gene (which encodes for CSF-1R) is restricted to cells of the myeloid lineage and is a marker of macrophage differentiation (4). We have recently described the MacGreen transgenic mouse in which the promoter for the CSF-1R (c-fms) directs the expression of enhanced green fluorescent protein (EGFP) by all cells of the monocyte/macrophage lineage (5). In the current study, we used MacGreen and CSF-1-deficient osteopetrotic (op/op) mice to determine whether distinct subsets of DC could be distinguished by the differential expression of the CSF-1R or their developmental requirement for CSF-1 signaling.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

MacGreen mice were produced on a B6 x CBAF1 background as described previously (5). Homozygous op/op and heterozygous op/wt mice were supplied by the Herston Medical Research Centre (Brisbane, Australia). C57BL/6 mice were supplied by the Animal Resource Centre (Western Australia, Australia). All mice used were 5–12 wk of age.

Cytokine treatment

Recombinant progenipoietin-1 (ProGP-1) (Pfizer) was diluted in 1 µg/ml murine serum albumin in PBS before injection. Mice were injected s.c. with diluent or 20 µg/animal/day ProGP-1 once daily from days –7 to –1. Complete blood counts were performed on EDTA peripheral blood (PB) samples using a Sysmex SE-9000 (Sysmex) automated analyser.

Monoclonal Abs

The following mAbs were purchased from BD Pharmingen: FITC-conjugated CD11c (HL3) and IgG2a isotype control; PE-conjugated CD4 (GK1.5), CD8a (53-6.7), CD11b (M1/70), CD11c (HL3), CD40 (3/23), CD45R/B220 (RA3-6B2), CD80 (16-10A1), CD86 (GL1), I-A/I-E (2G9), and IgG2b isotype control; and PE-Cy5-conjugated CD8 CD4 and IgG2b isotype control. PE-conjugated CD115 was purchased from Serotec. Purified mAb against CD3 (KT3), CD19 (HB305), Gr1 (RB6-8C5), Thy1.2 (HO-13-4), Ter119, Fc{gamma}R II/III (2.4G2), and biotinylated F4/80 were produced in house.

Cell preparation

DC purification was undertaken as described previously (6). Briefly, low-density cells were enriched from digested lymphoid tissues, bone marrow, or lysis buffer-treated heparinized blood by Nycodenz density gradient centrifugation. In some experiments, non-DC lineage cells were depleted by coating with rat IgG Abs to B cells (CD19), T cells (CD3, Thy1), granulocytes (Gr-1), and erythroid cells (Ter-119). The coated cells were then removed by magnetic beads coupled to anti-rat IgG (Dynal ASA, Oslo, Norway). For mixed lymphocyte cultures (MLC), splenic T cells were purified by depleting B cells (B220 and CD19), monocytes (CD11b), granulocytes (Gr-1), and erythroid cells (Ter-119) using magnetic bead depletion. For culture experiments, highly purified DC populations (>98%) were obtained by FACS (MoFlo; DakoCytomation). Peritoneal cells were lavaged from the peritoneal cavity with HBSS containing EDTA (Sigma-Aldrich).

Real-time RT-PCR for CSF-1R

For real-time RT-PCR analysis, equivalent numbers of sort-purified cells were resuspended in TRIzol (Invitrogen Life Technologies), snap frozen on dry ice, and RNA extracted, according to the manufacturers protocol. cDNA was immediately reverse transcribed using avion myeloblastosis reverse transcriptase (Promega), according the manufacturers protocol, and cDNA stored at –20°C. Real-time PCR was undertaken using Platinum SYBR Green qPCR SuperMix UDG (Invitrogen Life Technologies) conducted on a Rotor-Gene3000 (Corbett Research) and data analyzed using Rotor-Gene v5.0 (Corbett Research). Primers used for CSF-1R reactions were 5'-CCACCATCCACTTGTATGTCAAAGAT-3' (forward) and 5'-CTCAACCACTGTCACCTCCTGT-3' (reverse). Primers used for {beta}2-microglobulin reactions were 5'-TTTCTGGTGCTTGTCTCACTGACCG-3' (forward) and 5'-GCAGTTCAGTATGTTCGGCTTCCCA-3' (reverse). The thermal cycler conditions were as follows: 1 x 2 min 50°C, 1 x 10 min 95°C, 40–50 cycles denaturation (15 s, 95°C), and combined annealing/extension (1 min, 60°C). CSF-1R cDNA copy numbers were then normalized for variations in the efficiency of RNA extraction and cDNA transcription against the {beta}2-microglobulin housekeeping gene.

Cell culture

Sort-purified CD11c+c-fms/EGFPneg PB cells were cultured at 106/ml for 7–9 days in 10% FCS/IMDM (JRH Biosciences) supplemented with GM-CSF, IL-3, and IL-4 (all at 100 ng/ml). Sort-purified CD11chigh and CD11cdimB220+ DC were cultured for 18 h at 106/ml in 10% FCS/IMDM supplemented with GM-CSF, IL-3 (each at 100 ng/ml), LPS (1 µg/ml), and phosphorothioated oligo CpG (1668; 0.5 µM) (7). For MLC, 106 magnetic bead-purified C57BL/6 T cells were cultured for 5 days with varying numbers of sort-purified CD11chigh DC. [3H]Thymidine (1 µCi/well) was added on day 4, and proliferation was determined 18 h later using a Betaplate Reader (Wallac).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
CD11chigh and CD11cdimB220+ DC express c-fms

We first compared c-fms expression by peritoneal macrophages and splenic DC subsets using three-color flow cytometry. For these experiments, DC were highly enriched from MacGreen and C57BL/6 spleens by density gradient centrifugation and magnetic bead depletion of lineage-positive cells. CD11chigh (myeloid) and CD11cdimB220+ (plasmacytoid) cells were gated (Fig. 1a) and examined for c-fms transgene reporter expression. Peritoneal F4/80+ macrophages and both DC subsets in MacGreen mice expressed c-fms/EGFP; however, the level of expression in the F4/80+ macrophages and the CD11chigh DC was higher than that of the CD11cdimB220+ DC subset (Fig. 1b). In contrast to F4/80+ macrophages, which expressed high levels of surface CSF-1R using a CD115 mAb, only low-level surface CSF1R was detected on either DC subset, and again, the CD11chigh DC staining was brighter than that of the CD11cdimB220+ DC subset (Fig. 1b). The differential expression of CSF-1R by peritoneal F4/80+ macrophages and the two DC subsets was confirmed by real-time PCR analysis. The expression of CSF-1R mRNA in F4/80+ macrophages was 5-fold that of CD11chigh DC, which was 2-fold higher than the CD11cdimB220+ DC. (Fig. 1c). As expected, CSF-1R mRNA was not detected in CD4+ T cells. Finally, the presence of the EGFP reporter gene in the MacGreen mice did not alter the stimulatory capacity of CD11c+ DC (Fig. 1d).



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  		FIGURE 1. Splenic CD11chigh and CD11cdim B220+ DC express c-fms. Splenic DC were enriched from MacGreen or C57BL/6 mice by gradient centrifugation and lineage depletion and CD11chigh and CD11cdimB220+ populations gated (a) and examined for c-fms/EGFP or CSF-1R (CD115) expression (thick line) (b). Negative controls (fine line) are from c-fms/EGFP-negative littermates or isotype control mAb, respectively. Peritoneal F4/80+ macrophages served as a positive control for c-fms/EGFP and CSF-1R expression. Normalized CSF-1R mRNA levels were determined by SYBR green real-time PCR analysis of total RNA isolated from sort-purified cell populations as described in Materials and Methods. Data are presented as mean values with SDs from triplicate samples and are representative of one of three independent experiments with similar results (c). The capacity of sort-purified wild-type or MacGreen CD11chigh DC to stimulate allogeneic (H-2b) T cell proliferation was determined in an MLC using [3H]thymidine incorporation as a readout (d).

 
Examination of EGFP expression within the skin, thymus, and lymph nodes from MacGreen mice revealed EGFP bright cells included cells with DC morphology. In this regard, within epidermal sheets, Langerhans cells were clearly demarcated by EGFP expression, whereas cells with pronounced interdigitating processes were evident within the thymic cortex. In addition to the strong expression of EGFP in the macrophages of the subcapsular sinus, note the extensive dendritic network of EGFP-positive cells through the remainder of the lymph node (Fig. 2).



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  		FIGURE 2. Tissue distribution of EGFP expression in MacGreen mice. Immunofluorescence from EGFP within epidermis, thymus, and lymph node (x400). Note the positive cells with Langerhans morphology within epidermal sheet and the extensive dendritic network of interdigitating GFP-positive cells through the thymic cortex and lymph node.

 
Because MacGreen mice permitted enhanced detection of c-fms promoter activity, we used these mice to extend our analysis of CD11c+ DC CSF-1R expression within various lymphoid organs. For these experiments, DC were enriched from lymphoid tissues by density gradient centrifugation. Greater than 90% of CD11c+ cells within DC preparations from bone marrow, thymus, spleen, and lymph nodes expressed c-fms/EGFP. In contrast, within the PB DC preparations, 20–30% of the CD11c+ cells were EGFP negative (Fig. 3), corresponding to ~6% of blood mononuclear cells.



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  		FIGURE 3. Expression of c-fms by DC subsets. DC from the various tissues of MacGreen mice were enriched by gradient centrifugation as described in Materials and Methods and examined for c-fms/EGFP expression using two-color flow cytometry. Quadrants were assigned using isotype control mAb (PE channel) and DC preparations from c-fms/EGFP-negative littermates (FITC channel).

 
PB contains a CD11c+c-fms/GFPneg DC precursor population

Because a CD11c+MHC-IIneg DC precursor population of similar frequency to that of the CD11c+c-fms/GFPneg PB population was recently identified in murine PB (8), we investigated whether the CD11c+c-fms/GFPneg PB population related to this DC precursor. To limit the number of animals required, we treated the MacGreen mice with ProGP-1, a chimeric protein with receptor agonist activity for both fetal liver tyrosine kinase-3 (Flt3) and G-CSF receptor that is known to expand both CD11chigh and CD11cdimB220+ DC in blood and lymphoid organs (9, 10). ProGP-1 pretreatment of the MacGreen mice resulted in a 100-fold increase in the blood white cell count and a 40-fold expansion of blood CD11c+ DC, and this expansion was associated with both the CD11c+c-fms/GFPpos and CD11c+c-fms/GFPneg populations (Fig. 4a). Phenotypic analysis of the CD11c+c-fms/GFPneg population from ProGP-1-treated animals revealed the cells to be MHC class IIneg, CD8neg, CD4neg, F4/80neg, CD11b+, CD62Ldim, and B220+ (Fig. 4b). Notably, this phenotype is identical to that of the DC precursor described by del Hoyo (8).



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  		FIGURE 4. PB contains a CD11c+c-fms/EGFPneg DC precursor population. MacGreen mice were treated with control diluent or ProGP-1, and white counts were determined as described in Materials and Methods. c-fms/EGFP expression was then determined in CD11c+ populations using two-color flow cytometry (a). Phenotypic analysis of the CD11c+c-fms/EGFPneg population (R2 in a above) by three-color flow cytometry using a panel of Ag-specific mAb (thick line). Isotype control mAbs are shown as a fine line (b).

 
Because the PB DC precursors have been shown to exhibit the capacity to reconstitute all splenic DC populations, we examined whether the differentiation of CD11c+c-fms/GFPneg population would induce the expression of c-fms/EGFP. Following 7–9 days in culture in the presence of GM-CSF, IL-4, and IL-3, sort-purified CD11c+GFPneg DC precursors differentiated into large DC-like cells (based on forward and side scatter characteristics) and expressed c-fms/EGFP (Fig. 5).



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  		FIGURE 5. CD11c+c-fms/EGFPneg DC precursor up-regulates c-fms upon differentiation. Analysis of forward and side scatter characteristics and c-fms/EGFP expression by the CD11c+c-fms/EGFPneg population before (day 0, thin line) and after culture in vitro (day 7, shaded peak). Thick line depicts level of c-fms/EGFP expression by freshly purified PB CD11c+c-fms/EGFPpos DC.

 
All DC subsets are reduced in CSF-1-deficient op/op mice

Because CSF-1R was found to be associated with DC maturation, we asked whether CSF-1 signaling was required for the generation and/or differentiation of DC. For these studies, we used op/op mice, which have a null mutation in the CSF-1 gene that results in congenital osteopetrosis (11) due to a deficiency of osteoclasts and macrophages (12). As expected, F4/80-positive peritoneal macrophages were largely absent in op/op mice (Table I). Examination of DC within the op/op spleen revealed a 43 and 70% reduction in the CD11chigh DC and CD11cdimB220+ compartments, respectively, compared with the normal heterozygous op/wt littermates. In contrast, the relative frequency of the CD4+, CD8+, or CD4–CD8– subsets of the CD11chigh population was unchanged.


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  		Table I. Frequency and subset composition of splenic DC

 
DC cell function and maturation is not altered in op/op mice

Functional testing of sort-purified CD11chigh DC in MLC revealed that op/op DC were as potent at stimulating allogeneic T cell (C57/BL6) proliferation as normal heterozygote op/wt DC (Fig. 6a). Furthermore, following 18 h of culture in the presence of GM-CSF, IL-3, LPS, and CpG, op/op and op/wt CD11chigh DC class II and costimulatory molecule expression was equivalent (Fig. 6b). Interestingly, following culture, the op/op CD11cdimB220+ DC exhibited enhanced expression of CD40 and CD86 as compared with the op/wt CD11cdimB220+ DC.



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  		FIGURE 6. T cell stimulatory capacity of freshly purified op/op and op/wt CD11chigh DC. Freshly purified CD11chigh DC from op/wt and op/op (H-2b/k) spleens were cultured in the presence of allogeneic (H-2b) T cells and proliferation determined by [3H]thymidine incorporation (a). Costimulatory molecule expression by in vitro-matured op/wt and op/op DC subsets. Sort-purified DC subsets from op/wt and op/op spleens were cultured in the presence of GM-CSF, IL-3, LPS, and phosphorothioated oligo CpG. Cells were harvested after 18 h and stained with PE-conjugated mAb as indicated (b). Data are from one experiment and represents one of three sets of cultures of DC subsets derived from individual op/wt and op/op spleens.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
DC represent a heterogeneous population whose lineage relationship with other hemopoietic cell populations has long been questioned. Although DC were initially thought to be of myeloid origin, several recent studies using DC reconstitution experiments have established that both common myeloid and lymphoid precursors exhibit the capacity to differentiate into DC in vivo. However, the relative contribution of either of these precursor populations during normal DC development is not known. DC can be subdivided into multiple subsets based on phenotype and tissue distribution. Thus, within mouse spleen four unique CD11c+ DC subsets (CD8+, CD4+, CD8–CD4–, and B220+) can be identified. Furthermore, DC populations include Langerhans cells and dermal DC within the skin and CD8int DC within lymph nodes. Although the various DC subpopulations appear to be developmentally and functionally distinct, it is not clear whether this divergence can be attributed to distinct lineages, different stages of development/activation, or the influence of unique tissue specific niches.

CSF-1 drives the expansion and differentiation of macrophages, which are well established to be of myeloid lineage. MacGreen mice express EGFP driven by the c-fms promoter, thus permitting identification of myeloid-derived cells. In this study, we demonstrate that the MacGreen mouse represents a highly sensitive means of amplifying CD115. This allowed assessment of the potential for expression of the CSF-1R and confirmed that the majority of all tissue DC subsets expressed c-fms/EGFP. Conversely, up to 30% of CD11c+ DC within the PB lacked c-fms/EGFP expression. The c-fms/EGFPnegCD11c+ PB population exhibited a phenotype (class IIneg, CD11b+, B220+, and CD62L+) identical to that of a previously described blood DC precursor (8) and could be induced to express c-fms/EGFP upon differentiation in vitro. Although the data suggest that these c-fms/EGFPnegCD11c+ cells are DC precursors, we cannot exclude the possibility that these are CD11c+ cells of a separate lineage (e.g., lymphoid) or stage of trafficking. However, these putative DC precursors resemble common myeloid progenitors purified from bone marrow in which control elements of the c-fms locus are assembled into active chromatin, and c-fms mRNA expression is very low (13). The expression of c-fms is induced rapidly during macrophage lineage commitment. In contrast to the intense c-fms/EGFP transgene expression seen in mature DC populations, surface c-fms (CD115) was expressed on DC at low levels only (3-log less than on F4/80-positive macrophages), suggesting that the majority of c-fms expression in DC is not surface bound. This finding does not imply that the CSF-1R is inactive. For example, Langerhans cells have been shown to express functional CSF-1R and respond to CSF-1 (14). c-fms mRNA is barely detectable in bone marrow myeloid progenitors, yet the cells are clearly CSF-1 responsive (13). Tissue macrophages express surface CSF-1R at much higher levels than proliferating progenitors, and in these cells, the receptor mediates endocytic clearance of the growth factor (15). The level of c-fms mRNA is also down-modulated posttranscriptionally by GM-CSF, which promotes DC differentiation (16, 17), and surface CSF-1R is down-modulated acutely by TLR agonists (18). In contrast, EGFP remains intracellular and therefore is not subject to variables that influence both initial expression at the surface and subsequent degradation. Therefore, the expression of the CSF-1R reporter gene is not expected to be perfectly correlated with the presence of the receptor on the cell surface. Taken together, these data suggest that expression of c-fms promoter activity is a marker of maturation within all DC subsets, and its absence identifies immature DC precursors within the PB.

DC numbers are reported to be normal in op/op mice, and previous studies have noted GM-CSF to be the primary cytokine determining DC development rather than CSF-1 (19, 20). In elegant studies of macrophage and DC differentiation in vitro, IL-6 from stromal cells has been shown to enhance CSF-1R expression on monocytes and promote CSF-1-CSF-1R internalization. This results in the subsequent differentiation of monocytes to macrophages (21). In contrast, TNF-{alpha} blocks CSF-1R expression and internalization, leading to DC differentiation (22). These data suggest that the absence of the CSF-1R expression would preferentially block macrophage differentiation, consistent with the phenotype of the CSF-1 (op/op) and CSF-1R-deficient mice (23). Because previous studies used poorly quantitative immunohistological techniques and predate the description of DC subsets, we revisited the influence of CSF-1 on DC development in these mice using a quantitative approach encompassing the wider understanding of DC subset heterogeneity as published recently (24). These data confirm that the absence of CSF-1 results in a 50–70% reduction in DC numbers, supporting the view that the low levels of CSF-1R on DC are, indeed, functional. CSF-1 is also required for optimal production of osteoclasts, hence, the osteopetrotic phenotype of the op/op mice. However, the op/op mice recover relatively normal osteoclastogenesis with age, which is attributed to the ability of vascular endothelial growth factor-A and/or flt3 ligand, to provide partial compensation (25, 26). Both these ligands act through type III tyrosine kinase receptors closely related to c-fms. Given the biology of flt3 ligand as a DC promoter, it is very likely that it also provides partial compensation for the absence of CSF-1, and of course, GM-CSF (which actually cross-modulates CSF-1 signaling (27)) may also contribute to DC homeostasis in the absence of CSF-1.

The majority of splenic CD11chigh DC is myeloid in origin based on repopulation experiments and the relative frequency of myeloid vs lymphoid precursors in vivo (2). In normal mice these myeloid DC can be further divided into CD4+, CD8+, and CD4–CD8– subsets (6), and while the relative generation of these subsets is not dependent of CSF-1 signaling, the optimal generation of CD11chigh myeloid DC in total does require CSF-1 (Table I). Although we were unable to document a functional defect in the ability of myeloid DC to stimulate allogeneic T cell responses, this does not exclude more subtle defects, and therefore, we are currently studying the functional characteristics of DC from op/op mice in detail. DC have been proposed as a separate lineage to monocytes and macrophages based on the absence of CSF-1R on PB and bone marrow-derived DC (28, 29). However, more recently the CSF-1R was reported to be expressed on monocytes before their differentiation to DC and the down-regulation of CSF-1R by TNF-{alpha} appears to be a critical component in driving DC (as opposed to macrophage) development (22). Our data confirm and highlight the differential expression of CSF-1R on macrophages and DC, and we propose that the differentiation of each lineage is at least in part determined at the cellular level by c-fms expression. Furthermore, the expression of c-fms by both myeloid and plasmacytoid DC and their dependence on CSF-1 as seen by the current studies in op/op mice also favors a common lineage for these two DC subsets. Recent studies confirming the ability of plasmacytoid DC to differentiate into myeloid DC following stimulation by dsRNA and type I IFNs further supports this concept of plasticity within DC subset lineages and their differentiation (30). Thus, although both common myeloid and lymphoid progenitors can give rise to both plasmacytoid and myeloid DC in vivo, these subsets can no longer be unambiguously defined on arbitrary assumptions of lineage (reviewed in Ref. 31). Our data provides further support of this concept, suggesting that the majority of tissue DC are of myeloid origin during steady state and that a close relationship between DC and macrophage biology exists in vivo.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by grants from the National Health and Medical Research Council and Queensland Cancer Fund. G.R.H. is a Wellcome Trust Senior Overseas Research Fellow. Back

2 Address correspondence and reprint requests to Dr. Kelli MacDonald, Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, Australia. E-mail address: kelliM{at}qimr.edu.au Back

3 Abbreviations used in this paper: DC, dendritic cell; EGFP, enhanced green fluorescent protein; op/op, osteopetrotic; ProGP-1, progenipoietin-1; PB, peripheral blood; MLC, mixed lymphocyte culture; Flt3, fetal liver tyrosine kinase-3. Back

Received for publication November 8, 2004. Accepted for publication May 13, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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