Published online before print September 5, 2008, doi: 10.1161/CIRCRESAHA.107.172718
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© 2008 American Heart Association, Inc.
Molecular Medicine |
The Wnt Antagonist Dickkopf-1 Mobilizes Vasculogenic Progenitor Cells via Activation of the Bone Marrow Endosteal Stem Cell Niche
From the Departments of Internal Medicine III (A.A., C.H., C.U., A.O., A.M.Z., S.D.) and Neurology (S.L.), J.W. Goethe University, Frankfurt, Germany; Weizmann Institute of Science (O.K., T.L.), Department of Immunology, Rehovot, Israel; and Pathology Associates (C.I.), Frankfurt, Germany.
Correspondence to Alexandra Aicher, MD, Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. E-mail aicher_a{at}yahoo.com
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Abstract |
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Therapeutic mobilization of vasculogenic progenitor cells is a novel strategy to enhance neovascularization for tissue repair. Prototypical mobilizing agents such as granulocyte colony-stimulating factor mobilize vasculogenic progenitor cells from the bone marrow concomitantly with inflammatory cells. In the bone marrow, mobilization is regulated in the stem cell niche, in which endosteal cells such as osteoblasts and osteoclasts play a key role. Because Wnt signaling regulates endosteal cells, we examined whether the Wnt signaling antagonist Dickkopf (Dkk)-1 is involved in the mobilization of vasculogenic progenitor cells. Using TOP-GAL transgenic mice to determine activation of β-catenin, we demonstrate that Dkk-1 regulates endosteal cells in the bone marrow stem cell niche and subsequently mobilizes vasculogenic and hematopoietic progenitors cells without concomitant mobilization of inflammatory neutrophils. The mobilization of vasculogenic progenitors required the presence of functionally active osteoclasts, as demonstrated in PTP
-deficient mice with defective osteoclast function. Mechanistically, Dkk-1 induced the osteoclast differentiation factor RANKL, which subsequently stimulated the release of the major bone-resorbing protease cathepsin K. Eventually, the Dkk-1–induced mobilization of bone marrow–derived vasculogenic progenitors enhanced neovascularization in Matrigel plugs. Thus, these data show that Dkk-1 is a mobilizer of vasculogenic progenitors but not of inflammatory cells, which could be of great clinical importance to enhance regenerative cell therapy.
Key Words: Wnt signaling • angiogenesis • vasculogenesis • bone marrow microenvironment
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Introduction |
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The formation and the repair of new adult blood vessels relies on the proliferation and migration of preexisting vessels (angiogenesis), as well as the mobilization of bone marrow–derived cells (vasculogenesis),1 including endothelial and pericyte progenitor cells.2–4 The vasculogenic capacity of bone marrow–derived cells acting as vascular modulators may in part rely on the secretion of angiogenic growth factors without being necessarily integrated into vessels.5,6
Therapeutic vasculogenesis holds promise to ameliorate ischemic diseases.7–12 This approach involves neovascularization by vasculogenic progenitor cells that are mobilized from the bone marrow for tissue regeneration. However, classic mobilizing agents, such as granulocyte colony-stimulating factor (G-CSF), induce a concomitant, potentially hazardous mobilization of inflammatory cells. Thus, there is a definitive need to search for novel, more specific mobilizers of vasculogenic progenitor cells.13 In the stem cell niche of the bone marrow, mobilization is tightly regulated in close proximity to the endosteal surface, which defines the interface of bone and bone marrow. This endosteal niche consists of various cell types including the bone-forming osteoblasts and the bone-resorbing osteoclasts. Whereas osteoblasts regulate hematopoiesis,14,15 osteoclasts, as well as the release of the cytokine RANKL, which increases osteoclastogenesis, were associated with mobilization of hematopoietic progenitor cells.16
Wnts comprise a large family of secreted lipid-modified glycoproteins that regulate multiple processes in a context and cell type–specific manner. In the bone marrow, activation of canonical Wnt signaling was shown to enhance hematopoietic progenitor cell self-renewal and controls osteoblast differentiation.17–20 Canonical Wnt signaling slows terminal osteoblast differentiation,21 whereas blockade of canonical Wnt signaling promotes late-stage osteoblast differentiation and stimulates the release of RANKL.20–24 Because RANKL plays a crucial role in hematopoietic progenitor cell mobilization, we examined whether the Wnt antagonist Dickkopf (Dkk)-1 affects the endosteal niche and regulates vasculogenic progenitor cell mobilization.
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Materials and Methods |
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Matrigel Plug In Vivo Assay
To determine the effect of Dkk-1 on neovascularization of Matrigel plugs in vivo, 0.5 mL of growth factor–enriched Matrigel (BD) supplemented with 40 U/mL heparin (Ratiopharm) and 0.5 to 1.5 µg/mL murine basic fibroblast growth factor (R&D Systems) was injected subcutaneously into 129/SvImJ mice (Charles River, Sulzbach, Germany). The day after the Matrigel implantation, Dkk-1 was either systemically injected (intraperitoneally) for 3 consecutive days or directly dissolved (100 ng Dkk-1 per 0.5 mL gel) in the Matrigel plugs. On day 7, Matrigel plugs were excised and blood vessel infiltration of the Matrigel plugs was visualized using paraffin sections stained for Griffonia simplicifolia lectin I (biotinylated isolectin B4; Vector Laboratories, Burlingame, Calif, followed by Alexa Fluor 555-conjugated streptavidin from Invitrogen, Karlsruhe, Germany). For some experiments, 200 µL of Griffonia simplicifolia lectin I (fluorescein-labeled; 1 mg/mL) was intravenously administered 30 minutes before euthanasia. The number of vessels per microscopic field was determined. All animal experiments were approved by the Institutional Animal Care and Use Committees of the Regierungspraesidium Darmstadt, Germany, and of the Weizmann Institute, Israel.
An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
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Results |
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Dkk-1 Mobilizes Vasculogenic Progenitor Cells
To investigate the effect of the Wnt inhibitor Dkk-1 on the mobilization of distinct cell populations, mice were injected with recombinant Dkk-1 or G-CSF as a positive control. Dkk-1 augmented the number of sca-1+flk-1+ and sca-1+c-kit+ progenitor cells in the peripheral blood, respectively (Figure 1a and 1b). Simultaneously, Dkk-1 increased the number of proliferating BrdU+sca-1+c-kit+ progenitors in the bone marrow (Figure I in the online data supplement). Moreover, Dkk-1 also enhanced the formation of vasculogenic colonies in a time- (Figure 1c) and dose-dependent (Figure 1d) manner. Dkk-1 induced a maximal vasculogenic progenitor cell mobilization between day 4 and day 7 with a dose of 0.5 mg/kg.
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4). Day 2 indicates mice euthanized after a single injection of Dkk-1 or PBS on day 1; Day 4, mice euthanized on day 4 after 3 consecutive injections of Dkk-1 or PBS on day 1 to 3; Day 7, mice euthanized on day 7 after 3 consecutive injections of Dkk-1 or PBS on day 1 to 3. Concentration of Dkk-1 used here and in the following experiments was 0.5 mg/kg unless stated otherwise. c, Time course of Dkk-1–induced spleen-derived vasculogenic colonies (nThe extent of the mobilization of vasculogenic progenitor cells achieved after injection of Dkk-1 was comparable to the established mobilizing cytokine G-CSF (Figure 1d). However, in contrast to G-CSF, which induced a strong mobilization of mature Gr-1+CD45+ neutrophils and CD11b+CD45+ myeloid cells from the bone marrow by day 4, Dkk-1 did not significantly increase the number of circulating inflammatory Gr-1+CD45+ cells and CD11b+CD45+ cells (Gr-1+CD45+/CD45+: 0.38± 0.03 [PBS]; 0.33±0.03 [Dkk-1]; 0.62±0.04 [G-CSF], P<0.01 versus PBS; CD11b+CD45+/CD45+: 0.23±0.04 [PBS]; 0.21±0.04 [Dkk-1]; 0.44±0.06 (G-CSF), P<0.05 versus PBS) (Figure 1e and 1f). Taken together, these results indicate that Dkk-1 selectively mobilizes progenitor cells but not circulating inflammatory cells.
Dkk-1 Stimulates Neovascularization
Because vasculogenic progenitors are known to increase neovascularization by physically incorporating into newly formed vessels and providing growth factors to support neovascularization in a paracrine manner,25–29 we determined the effect of Dkk-1 on vessel growth in an in vivo Matrigel model. Systemic administration of Dkk-1 resulted in a significant increase in vessel growth, as determined by the number of vasculogenic lectin+ cells (Figure 2a through 2d), invading vessel-like structures (supplemental Figure II), and smooth muscle actin–positive cells (supplemental Figure III) as compared to PBS-treated controls. Consistently, the hemoglobin content of the Matrigel plug was significantly augmented after systemic Dkk-1 injection (Figure 2e), indicating an increased blood supply. To assess the contribution of bone marrow–derived cells after Dkk-1 treatment, we used the Matrigel model in mice receiving bone marrow transplantation with GFP+ transgenic bone marrow cells (Figure 2f and 2g). In untreated mice, the number of newly formed vessels and the incorporation of bone marrow–derived GFP+ cells was very low. In contrast, the tracking of GFP+lectin+, GFP+ CD31+, and GFP+von Willebrand factor+ cells in the Matrigel plugs after Dkk-1 treatment suggests the bone marrow contribution of invading vessels (Figure 2f and 2g and supplemental Figures III and IV). Of note, several GFP+ cells were also detected in perivascular areas, some of which were expressing smooth muscle actin (supplemental Figure III).
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Because Wnt signaling has been shown to inhibit angiogenesis in vitro,30 we also tested the effect of the Wnt antagonist Dkk-1 on endothelial sprouting in vitro and in vivo. In vitro, Dkk-1 increased human umbilical vein endothelial cell (HUVEC) sprouting (100 ng/mL human Dkk-1: 209±33.2%, P<0.01, n=9 to 10), whereas human Dkk-1 siRNA inhibited HUVEC sprouting (35.5±6.0% of the baseline level; P<0.05; n=4 to 5) (see also supplemental Figure V). Likewise, the early presence of Dkk-1 in vitro augmented the number of vasculogenic progenitor colonies (supplemental Figure VI). In vivo, local delivery of Dkk-1 in the Matrigel plugs resulted in an increased vessel ingrowth (Figure 2e). However, the effect of local Dkk-1 application was only 54.5% compared to the effect of systemic injection indicating that Dkk-1 elicits systemic effects in addition to a local activation of angiogenesis. Thus, these data suggest that the profound augmentation of neovascularization seen in vivo in our Matrigel experiments using intraperitoneal injections of Dkk-1 seem to be mediated both via systemic mobilizing effects and direct vasculogenic effects of Dkk-1.
Dkk-1 Suppresses Wnt Signaling in Bone Marrow Endosteal Cells
To identify the molecular effects of Dkk in the bone marrow, we used TOP-GAL transgenic mice carrying a β-galactosidase gene driven by a LEF/TCF/β-catenin responsive promoter, which reports the status of the transcriptional activity of β-catenin, the product of canonical Wnt signaling.31 Sites of active canonical Wnt signaling in untreated mice were identified by X-gal staining as endosteal cells, including osteoblasts, and a small number of hematopoietic cells (Figure 3a through 3c). Dkk-1 potently suppressed canonical Wnt signaling in endosteal cells (Figure 3b), suggesting that the bone marrow niche is indeed a target for Wnt antagonists such as Dkk-1. Consequently, we examined whether Dkk-1 affects typical Wnt target genes such as axin 2 (conductin).32 Indeed, inhibition of Wnt signaling in mice by Dkk-1 injections resulted in decreased expression of axin 2 in the bone marrow for up to 72 hours (Figure 3d and 3e). Similar results were obtained by incubating total bone marrow–derived cells with Dkk-1 ex vivo for 6 hours (Figure 3f). Thus, systemically administered Dkk-1 acts as an inhibitor of Wnt signaling in the bone marrow niche.
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Dkk-1 Stimulates the Expression of RANKL
Because the osteoblast-derived osteoclast differentiation factor RANKL was recently shown to mobilize hematopoietic progenitor cells without concomitant increase of inflammatory cells from the bone marrow,16 we determined the effect of Dkk-1 on RANKL expression. After treatment of mice with recombinant Dkk-1, RANKL expression was upregulated as determined by RT-PCR (Figure 4a and 4b). Moreover, Dkk-1 increased the number of osteoclasts in control mice, but not in young female PTP-deficient mice with a defective osteoclast function,33 which are irresponsive to RANKL (Figure 4c).16 These results suggest that Dkk-1 induces an increase in osteoclast numbers mediated by the osteoclast differentiation factor RANKL. Most notably, treatment of mice with recombinant RANKL also resulted in an increase in the number of vasculogenic colonies as compared to Dkk-1 (Figure 4d). In accordance with the recently published angiogenic effect of RANKL,34 systemically administered RANKL also significantly augmented neovascularization in Matrigel plugs at a comparable level to Dkk-1 and G-CSF (Figure 4e). Thus, RANKL mimics the effects of Dkk-1, suggesting that increased expression of RANKL in endosteal cells contributes to the effect of Dkk-1 to mobilize vasculogenic progenitors.
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Dkk-1–Mediated Mobilization of Vasculogenic Progenitors Depends on Cathepsin K
Proteases are essential for the mobilization of progenitor cells from the bone marrow niche. RANKL has recently been reported to induce the expression of the major bone-resorbing cysteine protease cathepsin K in osteoclasts,16 which cleaves adhesive bonds between stem and stromal cells in the bone marrow. Therefore, we tested whether cathepsin K expression was upregulated by Dkk-1. Indeed, an increase in mRNA (Figure 5a) and protein expression (Figure 5b) was observed in the bone marrow following 48 hours of daily Dkk-1 administration. Consistently, the Dkk-1–induced increase in the number of vasculogenic colonies was inhibited in the presence of the cysteine protease inhibitor E-64, suggesting that vasculogenic colony formation is at least in part dependent on cathepsin K (Figure 5c). In addition, the Dkk-1–induced increase in the number of vasculogenic colonies (Figure 5d) was suppressed in young female PTP-deficient mice. Young female PTP-deficient mice exhibit a mild defective osteoclast function without the limitation of osteopetrosis with extramedullary hematopoiesis as opposed to cathepsin K–deficient mice.35 Hence, these data further confirm the role of osteoclasts, which abundantly produce cathepsin K, for the mobilization of vasculogenic progenitors in a genetic knockout model.
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) between Dkk-1 vs baseline (PBS) injection (n=4). |
Discussion |
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In this report, we show that the Wnt antagonist Dkk-1 suppressed canonical Wnt signaling in bone marrow endosteal cells, suggesting a role for Dkk-1 in the regulation of the bone marrow stem cell niche. Intriguingly, Dkk-1 mobilized vasculogenic progenitor cells without concomitant release of inflammatory cells as compared to G-CSF. These effects are reminiscent of the recently described effect of RANKL.16 Indeed, Dkk-1 induced expression of the osteoclast differentiation factor RANKL and the bone-resorbing protease cathepsin K. Subsequently, the vasculogenic progenitor mobilizing effect of systemically administered Dkk-1 resulted in enhanced neovascularization in the Matrigel plug assay, because higher numbers of GFP+ transgenic bone marrow–derived cells were recruited to newly formed vessels. Therefore, Dkk-1 appears to be a potent regulator of vasculogenic progenitors.
The mechanisms by which Dkk-1 stimulates RANKL expression and mobilization of vasculogenic progenitors may include a direct effect on the RANKL promoter activity. Dkk-1 may unleash RANKL by inhibiting a β-catenin–dependent repression of the RANKL gene via TCF/LEF consensus binding sites in the 5' proximal region of the RANKL gene.24 Additionally, Dkk-1 could also block the β-catenin–dependent upregulation of osteoprotegerin, a physiological inhibitor of RANKL.20 These mechanisms, in turn, induce expression of the osteoclast differentiation factor RANKL, which then leads to secretion of the potent bone-resorbing protease cathepsin K. RANKL has been described as a regulator of cathepsin K expression via a calcineurin/NFAT-dependent pathway.36 The cysteine protease cathepsin K is intracellularly activated and secreted into the resorption lacuna, resulting in mobilization of bone marrow cells through proteolytic degradation of osteoblast-derived stromal cell–derived factor (SDF)-1, stem cell factor, and osteopontin, thereby, interfering with adhesive stem cell–stromal cell interactions.16,35,37 Of note, Dkk-1 can also deliver signals independent of β-catenin through noncanonical Wnt signaling.38
In addition to the recently published data16 showing that recombinant RANKL mobilized hematopoietic progenitors, we now provide evidence that Dkk-1 also mobilizes vasculogenic progenitors without concomitant inflammatory cells. Wnt signaling is well known to modulate the stem cell niche as well as directly affecting stem cell proliferation, expansion, and differentiation. Mimicking of canonical Wnt signaling by pharmacological inhibition of glycogen synthase kinase-3β was shown to enhance proliferation of hematopoietic stem cells. Therefore, one may expect that Dkk-1 might induce a reduction in the proliferative rate of bone marrow progenitor cells. However, we and others39 could show that Dkk-1 indeed stimulated the proliferation of progenitor cells in the bone marrow. The failure of Dkk-1 to block proliferation may be explained by the fact that Dkk-1 can only affect progenitor cells with an active Wnt signaling in contrast to pharmacological glycogen synthase kinase-3β inhibitors, which act downstream and independently of Wnt receptors and, thus, are likely to target a broader population of cells.19 Indeed, Wnt signaling in the bone marrow is modulated in a cell and context-specific manner. We observed that endogenous canonical Wnt signaling is preferentially localized to endosteal cells such as osteoblasts and is only active in a rather small percentage of hematopoietic bone marrow cells, as evaluated by β-gal+ cells in TOP-GAL reporter mice. Dkk-1, therefore, is likely to elicit its effects on vasculogenic progenitors indirectly via changing the activity of osteoblasts and subsequently upregulating cytokines such as RANKL. However, the question of why Dkk-1–induced RANKL does not induce mobilization of inflammatory cells still remains elusive. RANK/RANKL molecules belong to the TNF/TNF receptor family and are, therefore, activated by inflammatory agents and play a pathological role in inflammatory, as well as in malignant, conditions.40,41 However, the role of local RANKL production in the bone marrow and its involvement in the immune system under physiological conditions is not clear yet.42,43
The effects of Dkk-1 on mobilization of vasculogenic progenitors and subsequent enhancement of neovascularization could be of great clinical use to specifically enhance cell-based therapeutic vasculogenesis. In this respect, it is important to note that short-term application of Wnt activators appears to be safe.19 In contrast, excess canonical Wnt signaling by constitutive long-term activation has recently been reported to lead to hematopoietic stem cell impairment via stem cell exhaustion and multilineage blockade and, thus, should be avoided.44–46 Moreover, Wnt signaling plays a crucial (but double-edged role) in regulating stem cell differentiation and contributes to skeletal muscle regeneration.47,48 On the other hand, Dkk-1 has been recently reported to be involved in the cardiovascular lineage commitment.49 Furthermore, Dkk-1 antisense therapy has been shown to protect against estrogen deficiency-induced bone loss in a rat model by downregulating Dkk-1 and RANKL in osteogenic cells.50 Therapies directed against the Dkk-1 downstream targets RANKL and cathepsin K are currently under clinical investigation for the treatment of osteoporosis.51,52 However, one should keep in mind that antiosteoporosis therapies based on Dkk-1 inhibition may also result in a reduced mobilization of vasculogenic progenitor cells and, subsequently, impaired neovascularization processes, which may lead to undesired effects of the novel treatment concept.
Although the mechanism underlying the mobilization of non–bone marrow–derived vasculogenic progenitors is still unclear, it might be intriguing to speculate that Dkk-1 may also be able to mobilize these vasculogenic progenitors.53,54
Importantly, both Dkk-1 and G-CSF–mediated pathways converge at the level of osteoblasts. However, whereas Dkk-1 induces cathepsin K to cleave osteoblast-derived SDF-1, G-CSF reduces osteoblast numbers and activity to suppress SDF-1 production.16,55 Eventually, G-CSF mobilization also promotes neovascularization,56–58 most likely via vasculogenic progenitors but also by increasing inflammatory cells, notably neutrophils, which play an important role in angiogenesis.59 However, increasing levels of circulating inflammatory cells could potentially lead to atherosclerotic plaque growth and/or destabilization.60 Thus, the capacity of Dkk-1 to mobilize vasculogenic progenitors without the simultaneous involvement of inflammatory cells offers a unique potential for therapeutic vasculogenesis in ischemic atherosclerotic diseases. Moreover, the improvement in vasculogenic progenitor-mediated neovascularization, as observed after administration of Dkk-1 in the present study, may additionally contribute to the angiogenic and cardioprotective effects reported for other Wnt antagonists.61–63
Taken together, the Wnt antagonist Dkk-1 inhibited canonical Wnt signaling in bone marrow endosteal cells, suggesting a crucial role for the regulation of the endosteal stem cell niche. Dkk-1 appears to be a specific mobilizing agent for vasculogenic progenitors, which could be relevant to optimize regenerative cell therapy.
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Acknowledgments |
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We thank Marion Muhly-Reinholz, Ariane Fischer, Tino Röxe, and Andrea Knau for excellent technical assistance. We thank Prof Ari Elson for kindly providing PTP
KO mice. Sources of Funding
This work was supported by the Sonderforschungsbereich (SFB) 553 B6, the European Vascular Genomics Network, and the Leducq Foundation.
Disclosures
None.
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Footnotes |
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Original received January 24, 2008; revision received August 22, 2008; accepted August 27, 2008.
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