Published online before print December 4, 2003, doi: 10.1161/01.RES.0000110419.50982.1C
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© 2004 American Heart Association, Inc.
Cellular Biology |
Bone Marrow-Derived Cells Do Not Incorporate Into the Adult Growing Vasculature
From Max-Planck-Institut for Clinical & Physiological Research (T.Z., B.F., S.K., M.H., A.H., W.S.), Bad Nauheim, Germany, and Department of Internal Medicine (R.V.), University Hospital Giessen, Giessen, Germany.
Correspondence to Tibor Ziegelhoeffer, MD, Max-Planck-Institute for Clinical & Physiological Research, Benekestrasse 2, 61231, Bad Nauheim, Germany. E-mail t.ziegelhoeffer{at}kerckhoff.mpg.de
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Abstract |
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Bone marrow-Derived cells have been proposed to form new vessels or at least incorporate into growing vessels in adult organisms under certain physiological and pathological conditions. We investigated whether bone marrow-Derived cells incorporate into vessels using mouse models of hindlimb ischemia (arteriogenesis and angiogenesis) and tumor growth. C57BL/6 wild-type mice were lethally irradiated and transplanted with bone marrow cells from littermates expressing enhanced green fluorescent protein (GFP). At least 6 weeks after bone marrow transplantation, the animals underwent unilateral femoral artery occlusions with or without pretreatment with vascular endothelial growth factor or were subcutaneously implanted with methylcholanthrene-induced fibrosarcoma (BFS-1) cells. Seven and 21 days after surgery, proximal hindlimb muscles with growing collateral arteries and ischemic gastrocnemius muscles as well as grown tumors and various organs were excised for histological analysis. We failed to colocalize GFP signals with endothelial or smooth muscle cell markers. Occasionally, the use of high-power laser scanning confocal microscopy uncovered false-positive results because of overlap of different fluorescent signals from adjacent cells. Nevertheless, we observed accumulations of GFP-positive cells around growing collateral arteries (3-fold increase versus nonoccluded side, P<0.001) and in ischemic distal hindlimbs. These cells were identified as fibroblasts, pericytes, and primarily leukocytes that stained positive for several growth factors and chemokines. Our findings suggest that in the adult organism, bone marrow-Derived cells do not promote vascular growth by incorporating into vessel walls but may function as supporting cells.
Key Words: arteriogenesis • angiogenesis • bone marrow-Derived cells
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Introduction |
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In the embryo, the vascular system develops from mesodermal precursor cells called angioblasts, which invade the different embryonic organ primordia and ensemble in situ to form the primary capillary plexus. This process has been termed vasculogenesis. It is followed by sprouting and nonsprouting angiogenesis of the primary capillary plexus and additional differentiation, maturation, and remodeling, which finally result in the mature vascular system.1,2
Recently, the concept that vasculogenesis is restricted to embryonic life has been questioned. Bone marrow-Derived stem or endothelial progenitor cells have been proposed to circulate in adult organisms and to be recruited to and to incorporate into sites of physiological and pathological neovascularization.3,4 Furthermore, transplantation of these cells seems to augment recovery of perfusion and function in models of myocardial and peripheral ischemia.5–9 To differentiate endothelial progenitor or circulating/bone marrow-Derived cells from native endothelial cells in vivo, fluorescent carbocyanine DiI-labeled cells, as well as sex-mismatched and reporter gene-labeled cells isolated from bone marrow or from circulating blood, have been transplanted into recipient animals.3,5,10,11 The reported relative contribution of transplanted cells to the endothelium of growing vessels varies widely, from almost no incorporation to >50%.5,12 Moreover, some recent reports have raised doubts about the extent to which bone marrow-Derived cells trans-differentiate into organ-specific cells in adult organisms.13,14 Taking into account the methodological difficulties, the varying or even contradictory results, and the many unanswered questions concerning the possible mechanisms, the role of bone marrow-Derived cells in organ or vascular repair and growth has remained enigmatic.
Most animal studies involving resection or ligation of a femoral artery have focused on the incorporation of precursor cells into capillaries in the distal ischemic hindlimbs.3,5,11 However, there is much evidence to suggest that after occlusion of a major artery, the growth of true bypass collateral arteries is necessary to restore bulk blood flow.15–17 This process, called arteriogenesis, occurs by outward remodeling of preexistent interarterial connections. Monocytes/macrophages that have been found to accumulate around growing collateral vessels have long been speculated to be involved in arteriogenesis, and more recent evidence has corroborated their role.17–19 They have been hypothesized to be the source of growth factors, cytokines, and various proteases.17,20–22 More recently, infusion of other circulating cells, including even platelets, has been found to augment restoration of flow after arterial occlusion.23 Thus, a variety of circulating cells may play a role in collateral artery growth.
The present study was designed to test whether circulating bone marrow-Derived cells incorporate into collateral arteries after femoral artery ligation. Furthermore, the incorporation of these cells into vessels in the distal ischemic hindlimb and in growing tumors was also studied. Additionally, we infused vascular endothelial growth factor (VEGF) to increase mobilization of bone marrow-Derived stem cells and investigate its possible effect on the incorporation rate. To distinguish circulation-derived cells from tissue-resident cells, we transplanted bone marrow from transgenic donors constitutively expressing enhanced green fluorescent protein (enhanced GFP) into lethally irradiated wild-type hosts. High-resolution laser scanning confocal microscopy was used to assess GFP-positive bone marrow-Derived cell incorporation into the vasculature. We show that GFP-positive cells of bone marrow origin accumulate around growing collateral arteries, in ischemic tissues, and in growing tumors. However, we have not found any incorporation into the endothelium or the tunica media of the vessels.
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Materials and Methods |
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The present study was performed with permission of the State of Hessen, Regierungspräsidium Darmstadt, according to section 8 of the German Law for the Protection of Animals. It conforms with the NIH Guide for the Care and Use of Laboratory Animals.
Bone Marrow Transplantation and Transgenic Mice
Wild-type recipient mice 11 to 14 weeks old (n=35) were lethally irradiated, and 3 to 5x106 bone marrow donor cells from C57BL/6-TgN(ACTbEGFP)1Osb transgenic littermates (Jackson Laboratories, Bar Harbor, Maine) were transplanted via tail vein injection. In this transgenic line, with an enhanced GFP cDNA under the control of a chicken ß-actin promoter and cytomegalovirus enhancer (cac/enhanced GFP), all of the tissues, with the exception of erythrocytes and hair follicle cells, appear green under excitation light.24 Success of bone marrow transplantation was evaluated in each transplanted mouse by flow cytometry analysis using a panel of monoclonal antibodies against CD3, CD4, CD8, CD11b, CD19, and F4/80. To test whether transplanted mice maintained the appropriate pool of progenitor/stem cells and responded adequately to physiological stimuli, we performed endothelial progenitor cell assays5 (EPC assay), colony-forming unit assays (CFU assay), and flow cytometry analysis (CD34+lin- cells) with and without stimulation with recombinant human VEGF (rhVEGF).
Animal Model
Mouse Model of Hindlimb Ischemia
All surgical procedures were performed as described previously.15,17,19 Briefly, the recipient mice were anesthetized, and the femoral artery was ligated just distal to the origin of the deep femoral artery and proximal to the popliteal artery. Additionally, one group of animals was pretreated with 10 µg/d rhVEGF IP for 1 week before the surgical procedure. Relative blood flow and hemoglobin oxygen saturation measurements in the mouse feet were performed before, immediately after, and on the third and seventh postoperative day using a laser Doppler perfusion imager and AbTisSpec TM spectrometer, respectively. The right-to-left, ie, ligated-to-nonligated side, perfusion and hemoglobin oxygen saturation ratios were calculated for each mouse, and the results were expressed as mean±SEM.
In Vivo Model of Tumor Growth
Methylcholanthrene-induced fibrosarcoma (BFS-1) cells25 were grown in RPMI containing 10% FCS, 1% penicillin/streptomycin, 1% pyruvate, and 2% glutamine. Confluent monolayers were washed with PBS and trypsinized, and the cell suspension was collected by centrifugation. The cells were resuspended in DMEM+, and 1.5x106 cells/50 µL were injected subcutaneously into the back of the recipient mice. Three weeks after injection, the tumors were excised and processed for histological analysis.
Perfusion Fixation and Tissue Sampling
At days 7 and 21 after surgery, the mice were euthanized and the thoracic aorta was cannulated and perfused at 100 mm Hg with PBS buffer containing 0.1% adenosine plus 0.05% BSA followed by fixative (3% buffered paraformaldehyde). In this model, collateral arteries follow a constant course on the surface of the adductor muscles, which allows their identification in histological preparations.15,17,19 Thus, the adductor muscles containing the growing collateral arteries as well as gastrocnemius muscles from the ligated and nonligated sides were excised and processed for histological examination.
Histological Analysis
To assess incorporation of bone marrow-Derived cells into the vasculature, we looked for GFP-positive cells in paraffin or cryosections of adductor and gastrocnemius muscles, tumors, spleen, intestine, heart, lung, liver, and kidney of transplanted animals. The tissue samples were postfixed and either embedded in paraffin or cryopreserved. Five- to ten-micrometer-thick sections were immunostained with cell-specific (Bandeiraea simplicifolia [BS-1] lectin, 
-actin, vimentin, CD45, F4/80, CD3, CD34, and CD31) or cytokine-specific (monocyte chemoattractant protein-1 [MCP-1], granulocyte-macrophage colony-stimulating factor [GM-CSF], placenta growth factor [PlGF], fibroblast growth factor-2 [FGF-2], and VEGF) antibodies, and the immunoreactions were visualized using Leica DMLD fluorescence microscope or Leica TCS SP laser scanning confocal microscope. In some cases, after immunostaining and fluorescence analysis, the sections were stained with H&E to additionally identify GFP-positive cells. In addition, the numbers of GFP-positive cells in the adventitia of collateral arteries of mice with occluded and nonoccluded femoral arteries were quantified in arterial segments (minimum of 0.3 mm) using consecutive transversal paraffin sections.
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
Statistics
Statistical analyses were performed with Student’s t test. Differences were considered to be statistically significant if P<0.05.
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Results |
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Bone Marrow Transplantation
To test the efficiency of bone marrow transplantation into lethally irradiated mice, we analyzed blood from recipients up to 6 months after transplantation. As measured by their fluorescence intensity (flow cytometry), 79% to 86% of nucleated cells expressed eGFP 6 weeks after bone marrow transplantation and 85% to 93% after 6 months, indicating that most of the original stem-cell population was replaced by donor cells (Figures 1A and 1B). Furthermore, we compared the proportion of leukocyte subpopulations between transplanted and nontransplanted mice (flow cytometry). No difference between both groups was observed, confirming that the cell counts were within a physiological range at the time of surgery. To additionally evaluate whether transplanted mice do have an appropriate pool of stem/progenitor cells, we performed CFU assays, EPC assays, and flow cytometry analyses of peripheral blood with or without stimulation of bone marrow with rhVEGF. In CFU assay, the number of colonies obtained from bone marrow of transplanted mice did not differ from those from nontransplanted control mice (Figures 1E and 1F). Using EPC assays, we observed a comparable number of adherent cells staining positive for endothelial cell markers (BS-1 lectin and CD31) in samples from transplanted mice versus samples from control animals. The number of EPCs in peripheral blood increased after treatment with rhVEGF (Figure 1G). Flow cytometry analysis confirmed the presence of circulating CD34+lin- progenitor cells in the blood of transplanted mice (Figures 1C and 1D).
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After femoral artery occlusion, the gross appearance and functionality of the limbs of transplanted and nontransplanted mice were similar. Measurements of perfusion of the distal hindlimbs by laser Doppler imaging revealed no significant differences between the nontransplanted wild-type and bone marrow-transplanted groups of animals before (0.99±0.03 versus 0.99±0.04), immediately after (0.23±0.07 versus 0.26±0.07), and on days 3 (0.49±0.09 versus 0.53±0.12) and 7 (0.91±0.07 versus 0.93±0.02) after the femoral artery ligation, indicating that neither the irradiation nor the bone marrow transplantation affected blood flow recovery at the time of histological evaluation (Figure 1H). Hemoglobin oxygen saturation measurements of the mice feet (1.01±0.01 versus 0.99±0.03 before, 0.35±0.11 versus 0.39±0.11 immediately after, 0.81±0.03 versus 0.83±0.02 on day 3, and 0.86±0.07 versus 0.92±0.03 on day 7 after femoral artery ligation) confirmed these findings.
Bone marrow-Derived Stem Cells in Arteriogenesis
Immunofluorescent examination of adductor muscles from transplanted mice containing growing collateral arteries from the limb with femoral artery occlusion (Figure 2A) and quiescent collateral arteries from the limb without occlusion (Figure 2B) revealed numerous GFP-positive cells in the interstitium of adductor muscles. GFP-positive cells were frequently present in the adventitia of collateral arteries and close perivascular space in both occluded and nonoccluded limbs. However, 21 days after surgery, the amount of GFP-positive cells in the perivascular space of growing collateral arteries on the occluded side was significantly higher compared with quiescent collateral arteries from the hindlimb without femoral artery ligation (Figures 2C through 2E). In addition, numerous GFP-positive cells were found around the femoral artery and vein, close to the area of occlusion (Figure 2F).
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The perivascular GFP-positive cells formed clusters that were in close contact with the vascular walls. However, we were not able to find any GFP-positive cells in the tunica media (colocalization with actin antibodies) nor in the endothelial layer (colocalization with BS-1 lectin or CD34 antibodies) of vessels. Although the number of EPCs in peripheral blood increased after VEGF treatment, VEGF-pretreated animals showed similar results in terms of GFP-positive cell incorporation into the vascular wall. In some cases, as shown in Figures 3A and 3B, false-positive results were detected when 7-µm-thick sections were analyzed (Figure 3A), probably because of overlapping of signals from adjacent cells. Closer examination of 1-µm-thick confocal slices revealed lack of colocalization in all of the areas analyzed (Figure 3B).
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Bone marrow-Derived Stem Cells in Angiogenesis
On the nonligated side, a few GFP-positive cells were found in the gastrocnemius and the adductor muscles with a similar frequency (data not shown). On the ligated side, dense infiltrates of GFP-positive cells were found. These muscles showed signs of ischemic alterations, including leukocyte infiltration and fibrosis. Many GFP-positive cells were found scattered in the tissue, often around arteries and capillaries (Figure 3C). However, no GFP-positive smooth muscle or endothelial cells could be detected after a serial examination of the tissue stained with actin and CD31 antibodies or BS-1 lectin by confocal microscopy.
To additionally evaluate the contribution of bone marrow-Derived cells to angiogenesis, we used a model of tumor growth. The vasculature of the tumors was composed of vessels with different sizes deprived of a smooth muscle layer. GFP-positive endothelial cells were never found in these vessels (Figure 3D). Around the tumors, many feeding vessels showed GFP-positive cells in the adventitia, but again, they were never found incorporated into the media or endothelium (not shown).
Cell Type of Bone marrow-Derived Cells
Most of the GFP-positive cells detected in the different organs analyzed were found scattered in the interstitium and around vessels. The shape, localization, distribution, and morphology of these cells suggested that they are leukocytes, fibroblasts, and pericytes. Immunofluorescent staining with vimentin antibodies revealed that some interstitial spindle-shape GFP-positive cells are fibroblasts (Figures 4A and 4B). However, most GFP-positive cells accumulating in ischemic gastrocnemius muscles (Figures 4C and 4D) and in the adventitia of growing collateral arteries (Figures 4E and 4F) were identified as leukocytes by their positive staining with the pan-leukocyte marker CD45. Additional characterization of CD45-positive cells revealed that most leukocytes are F4/80-positive monocytes/macrophages (Figures 5A and 5B), whereas some are CD3-positive T-lymphocytes (Figures 5C and 5D). Immunolabeling for CD34 revealed specific signals confined occasionally to some endothelial cells and perivascular cells (Figures 6A and 6B). CD31 signals were detected in all vascular endothelial cells and rarely in some GFP-positive perivascular cells (Figures 6C and 6D).
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10%) of the CD45-positive cells are GFP-negative (arrows), which corresponds well with the data obtained by flow cytometry (see
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Given the prevalent association of bone marrow-Derived cells with growing collateral arteries and the previously reported stimulatory effect of chemokines like MCP-126 and GM-CSF27 on arteriogenesis, we explored the expression of several cytokines and growth factors in growing collateral arteries and perivascular leukocytes by immunoconfocal microscopy. Specific FGF-2 immunofluorescent signals were mainly detected in GFP-positive perivascular cells accumulating around growing collateral arteries (Figures 7A and 7B). Likewise, VEGF immunofluorescent signals were also detected in perivascular GFP-positive leukocytes (Figures 7C and 7D). However, the number of VEGF-positive cells was clearly lower than FGF-2. Despite the previously reported influence of PlGF on arteriogenesis,28 we did not detect this growth factor by immunofluorescent methods (data not shown). Likewise, GM-CSF was not found in growing collateral arteries or surrounding tissue (data not shown). However, we found strong and specific localization of MCP-1 in endothelium and adventitia of growing collateral arteries (Figures 7E and 7F). In addition, most GFP-positive perivascular leukocytes showed strong MCP-1 immunoreactivity.
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Discussion |
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Several studies have suggested that a variety of circulating cells, including monocytes and monocytoid potential stem or precursor cells as well as leukocytes and platelets, promote the recovery of perfusion in ischemic animal models.3,5,7,8,11,23,29,30 The main objective of this study was to investigate whether these positive effects are related to the incorporation of circulating cells into growing vessels, particularly into collateral arteries, which are essential for restoring bulk blood flow after arterial occlusion. To track and distinguish the cells of bone marrow origin from the tissue-resident ones, we transplanted lethally irradiated C57BL/6J mice with bone marrow from their eGFP-transgenic littermates. Using flow cytometry and histological analysis, we confirmed that all of the cells of transgenic animals, except those of hair cells and erythrocytes, constitutively express GFP (cac/eGFP), as previously reported.24 Six weeks and 6 months after transplantation, most (79% to 86% and 93%, respectively) nucleated cells in peripheral blood expressed GFP, thus confirming the successful bone marrow engraftment and hematopoietic reconstitution. Moreover, data obtained by CFU assays, EPC assays, and flow cytometry analysis indicate that progenitor and stem cells were present in the blood and the bone marrow of transplanted animals with proportions similar to nontransplanted mice and respond adequately to VEGF stimuli.
We performed a rigorous inspection of adductor muscles with growing collateral arteries, gastrocnemius muscles with ischemic and normoxic tissue, end-stage tumors, spleen, liver, heart, lung, kidney, and intestine using conventional fluorescence and high-power laser scanning microscopy to verify whether bone marrow-Derived cells transform into vascular cells under different physiological conditions. Endothelial and smooth muscle cell markers were used to confirm incorporation of these cells into growing or quiescent vasculature. Overall, at least 3000 sections were analyzed. We never found colocalization of GFP-signals with endothelial or smooth muscle cell markers. GFP-positive cells were frequently found in perivascular space and interstitium. These cells were identified as leukocytes, fibroblasts, and pericytes by shape and distribution in the tissue as well as by colocalization with specific markers (CD45 and vimentin). Additionally, we characterized the subsets of GFP- and CD45-positive leukocytes and found these cells to be mainly monocytes/macrophages and T lymphocytes, as identified by positive staining for F4/80 and CD3.
In the present study, we identified occasional GFP-positive cells colocalizing with CD31 and CD34 markers. It has been described that CD34 is expressed by hematopoietic progenitor cells, particularly by myelomonocytic colony-forming cells, endothelial progenitor cells, some mature endothelial cells, and monocytes. CD31 has been reported to be expressed by mature endothelial cells, myeloid precursor cells, CFU-macrophage precursor cells, and precursor cells for granulocytes. However, we failed to find GFP+CD34+ and GFP+CD31+ cells incorporated into the vascular wall. Thus, our data provide no evidence for the natural recruitment of bone marrow-Derived CD31/CD34-positive cells in the process of collateral artery growth. In some small arteries, conventional fluorescence microscopy and confocal microscopy using thick sections showed colocalization of the endothelial marker BS-1 lectin or the smooth muscle cell marker -actin with GFP signals. However, using high-resolution confocal microscopy, we show that overlapping of signals is attributable to the convolution of perivascular cells around vessels rather than colocalization of these signals in the same cell. Thus, in our experimental models of hindlimb ischemia and tumor growth, we have not found any evidence of postnatal vasculogenesis or an integration of bone marrow-Derived or circulating cells into the endothelium or tunica media of vessels.
To test whether the irradiation or bone marrow transplantation itself had influenced the incorporation of bone marrow-Derived cells into the vessel wall and thereby decelerate arteriogenesis, we performed relative blood flow and hemoglobin oxygen saturation measurements in the mouse feet before, immediately after, on days 3 and 7 after the femoral artery ligation. We did not observe any differences between transplanted and nontransplanted animals at any time point. Thus, we provide functional as well as morphological data that the incorporation of bone marrow-Derived cells into the vessel wall of growing collateral arteries and capillary vessels is not a natural event in the regeneration of the adult vascular system required for successful blood flow recovery after femoral artery ligation. Moreover, intraperitoneal administration of rhVEGF, which has been reported to promote mobilization of bone marrow-Derived stem cells,29,31 also did not lead to any demonstrable incorporation of GFP cells in the vasculature of these mice.
Despite the fact that we did not observe any incorporation of GFP cells into the vessel wall of transplanted mice, we did observe an accumulation of GFP-positive cells in the adventitia of growing collateral arteries in the proximal thigh and also in the ischemic distal hindlimb. Immunostainings with a panel of cell-specific antibodies indicate that these cells are mainly leukocytes, particularly belonging to monocyte/macrophage lineage (F4/80-positive cells) and, as we describe here for the first time, to the T-lymphocyte subpopulation (CD3-positive cells). Consequently, the question appears of whether these cells may act in a paracrine way, providing some growth factors or chemokines. Indeed, leukocytes have been previously suggested to play a critical role in arteriogenesis,17–21,26 probably by releasing activating cytokines, growth factors, and metalloproteinases and thereby creating an inflammatory environment necessary for the enhancement of collateral artery growth.15,16,22,28,32 Our present data support this hypothesis. We observed that the bone marrow-Derived GFP-positive cells clustered around growing collateral vessels secrete growth factors like FGF-2 and VEGF and chemokines like MCP-1, which had been previously shown to promote arteriogenesis.20,26
Our results are in agreement with some recent studies using laser-scanning confocal microscopy, suggesting that the transdifferentiation of bone marrow-Derived cells into organ-specific cells occurs less frequently than anticipated.13,14,33 On the other hand, numerous studies reported positive effects of endothelial progenitor or bone marrow-Derived cells on blood flow recovery using similar or related models of ischemic tissue revascularization.3,5,10,11 These effects were interpreted as a result of the incorporation of bone marrow-Derived cells into growing capillaries, even though collateral arteries bypassing the site of arterial occlusion are primarily responsible for blood flow recovery.15 Most of these studies used an approach where progenitor/stem cells were isolated, cultured, and infused into target organs and therefore not mimicking strictly the natural course of the cells infused. It has to be noted that the amount of naturally present bone marrow-Derived progenitors in the peripheral blood is very low, representing much less than 1% of cells in the circulation. Therefore, although the relatively moderate mobilization of bone marrow-Derived cells by application of VEGF did not lead to any incorporation of these cells into the vessel wall of growing arteries in our model, the amount of exogenous cells administered intravenously, intra-arterially, or intraperitoneally would be expected to exceed this number in magnitude, possibly leading to their incorporation. In addition, results of some recent studies have suggested differences in bone marrow and stem cell recruitment attributable to different organ lesions,37 suggesting that these cells may behave differently depending on the conditions and organs investigated. It is also possible that the isolation and subsequent culture of progenitor or bone marrow-Derived cells under special conditions can change the properties of these cells in terms of their capacity to incorporate into target tissue. Recently, it has been reported that in vitro cultured endothelial progenitor cells maintain the expression of monocyte/macrophage markers, such as CD11c, CD11b (Mac-1), CD14, and panleukocyte marker CD45,34–36 and are able to secrete some angiogenic factors, such as VEGF, hepatocyte growth factor, G-CSF, and GM-CSF. Therefore, it is possible that their in vivo observed proangiogenic effect might be at least partially attributable to the paracrine secretion of growth factors and chemokines.34
In conclusion, although we did not find any incorporation of circulating bone marrow-Derived cells in the endothelium and tunica media of growing vessels, we found a significant perivascular accumulation of GFP-positive cells in areas of collateral artery growth and capillary growth. Because these cells stained positive for some growth factors and chemokines, we suggest that their capability to promote vascular growth is unrelated to their structural incorporation but rather attributable to paracrine effects.
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Acknowledgments |
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This study was supported by grants from the Max-Planck-Gesellschaft (to T.Z. and W.S.) and from the Kerckhoff Clinic, Bad Nauheim (Forschungsprojekt PFOR-371 to S.K.). We thank Dr Schalch and Dr Jonas from the University of Giessen for their help with animal irradiation.
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Footnotes |
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Original received June 16, 2003; revision received November 21, 2003; accepted November 21, 2003.
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S. Zbinden, R. Zbinden, P. Meier, S. Windecker, and C. Seiler Safety and Efficacy of Subcutaneous-Only Granulocyte-Macrophage Colony-Stimulating Factor for Collateral Growth Promotion in Patients With Coronary Artery Disease J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1636 - 1642. [Abstract] [Full Text] [PDF]
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E. Toyota, D. C. Warltier, T. Brock, E. Ritman, C. Kolz, P. O'Malley, P. Rocic, M. Focardi, and W. M. Chilian Vascular Endothelial Growth Factor Is Required for Coronary Collateral Growth in the Rat Circulation, October 4, 2005; 112(14): 2108 - 2113. [Abstract] [Full Text] [PDF]
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L. C. Amado, A. P. Saliaris, K. H. Schuleri, M. St. John, J.-S. Xie, S. Cattaneo, D. J. Durand, T. Fitton, J. Q. Kuang, G. Stewart, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction PNAS, August 9, 2005; 102(32): 11474 - 11479. [Abstract] [Full Text] [PDF]
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D. Chalothorn, H. Zhang, J. A. Clayton, S. A. Thomas, and J. E. Faber Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H947 - H959. [Abstract] [Full Text] [PDF]
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H. F.R. Dohmann, E. C. Perin, C. M. Takiya, G. V. Silva, S. A. Silva, A. L.S. Sousa, C. T. Mesquita, M.-I. D. Rossi, B. M.O. Pascarelli, I. M. Assis, et al. Transendocardial Autologous Bone Marrow Mononuclear Cell Injection in Ischemic Heart Failure: Postmortem Anatomicopathologic and Immunohistochemical Findings Circulation, July 26, 2005; 112(4): 521 - 526. [Abstract] [Full Text] [PDF]
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B. Modarai, K.G. Burnand, B. Sawyer, and A. Smith Endothelial Progenitor Cells Are Recruited Into Resolving Venous Thrombi Circulation, May 24, 2005; 111(20): 2645 - 2653. [Abstract] [Full Text] [PDF]
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N. Ma, C. Stamm, A. Kaminski, W. Li, H.-D. Kleine, B. Muller-Hilke, L. Zhang, Y. Ladilov, D. Egger, and G. Steinhoff Human cord blood cells induce angiogenesis following myocardial infarction in NOD/scid-mice Cardiovasc Res, April 1, 2005; 66(1): 45 - 54. [Abstract] [Full Text] [PDF]
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M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF]
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D. Fukuda, M. Sata, K. Tanaka, and R. Nagai Potent Inhibitory Effect of Sirolimus on Circulating Vascular Progenitor Cells Circulation, February 22, 2005; 111(7): 926 - 931. [Abstract] [Full Text] [PDF]
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T. Tammela, B. Enholm, K. Alitalo, and K. Paavonen The biology of vascular endothelial growth factors Cardiovasc Res, February 15, 2005; 65(3): 550 - 563. [Abstract] [Full Text] [PDF]
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B. H. Annex and M. Simons Growth factor-induced therapeutic angiogenesis in the heart: protein therapy Cardiovasc Res, February 15, 2005; 65(3): 649 - 655. [Abstract] [Full Text] [PDF]
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M. Abedin, Y. Tintut, and L. L. Demer Mesenchymal Stem Cells and the Artery Wall Circ. Res., October 1, 2004; 95(7): 671 - 676. [Abstract] [Full Text] [PDF]
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I. Rajantie, M. Ilmonen, A. Alminaite, U. Ozerdem, K. Alitalo, and P. Salven Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells Blood, October 1, 2004; 104(7): 2084 - 2086. [Abstract] [Full Text] [PDF]
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E. Khmelewski, A. Becker, T. Meinertz, and W. D. Ito Tissue Resident Cells Play a Dominant Role in Arteriogenesis and Concomitant Macrophage Accumulation Circ. Res., September 17, 2004; 95(6): e56 - e64. [Abstract] [Full Text] [PDF]
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M. Heil and W. Schaper Influence of Mechanical, Cellular, and Molecular Factors on Collateral Artery Growth (Arteriogenesis) Circ. Res., September 3, 2004; 95(5): 449 - 458. [Abstract] [Full Text] [PDF]
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C. Urbich and S. Dimmeler Endothelial Progenitor Cells: Characterization and Role in Vascular Biology Circ. Res., August 20, 2004; 95(4): 343 - 353. [Abstract] [Full Text] [PDF]
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T. Kinnaird, E. Stabile, M. S. Burnett, and S. E. Epstein Bone Marrow-Derived Cells for Enhancing Collateral Development: Mechanisms, Animal Data, and Initial Clinical Experiences Circ. Res., August 20, 2004; 95(4): 354 - 363. [Abstract] [Full Text] [PDF]
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K. L. March and B. H. Johnstone Cellular approaches to tissue repair in cardiovascular disease: the more we know, the more there is to learn Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H458 - H463. [Full Text] [PDF]
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D. Skowasch, A. Jabs, B. Luderitz, and G. Bauriedel Bone Marrow-Derived Cells and Vascular Growth Circ. Res., April 30, 2004; 94(8): e71 - e71. [Full Text] [PDF]
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M. Heil, T. Ziegelhoeffer, B. Mees, and W. Schaper A Different Outlook on the Role of Bone Marrow Stem Cells in Vascular Growth: Bone Marrow Delivers Software not Hardware Circ. Res., March 19, 2004; 94(5): 573 - 574. [Full Text] [PDF]
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M. Heil, T. Ziegelhoeffer, S. Wagner, B. Fernandez, A. Helisch, S. Martin, S. Tribulova, W. A. Kuziel, G. Bachmann, and W. Schaper Collateral Artery Growth (Arteriogenesis) After Experimental Arterial Occlusion Is Impaired in Mice Lacking CC-Chemokine Receptor-2 Circ. Res., March 19, 2004; 94(5): 671 - 677. [Abstract] [Full Text] [PDF]
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