Published online before print March 30, 2006, doi: 10.1161/01.RES.0000219901.13974.15
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© 2006 American Heart Association, Inc.
Integrative Physiology |
Critical Roles of Muscle-Secreted Angiogenic Factors in Therapeutic Neovascularization
From the Departments of Cardiovascular Science and Medicine (K.T., T.M., H.T., H.A., S.T., T.K., H.M., T.O., K.M., J.-i.N., Y. Kobayashi, T.N., Y. Kuwabara, I.K.), Clinical Cell Biology (N.S., Y.S.), and Molecular Diagnosis (F.N.), Chiba University Graduate School of Medicine, Japan; and Division of Cell Biology (Y.I.), Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Japan.
Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp
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Abstract |
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The discovery of bone marrow–derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1ß (IL-1ß). We then examined an experimental model of limb ischemia using IL-1ß–deficient mice. Implantation of IL-1ß–deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1ß–deficient mononuclear cells increased expression of IL-1ß and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1ß markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.
Key Words: angiogenesis • interleukins • muscles
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Introduction |
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Peripheral vascular disease (PVD), mainly caused by atherosclerosis, leads to obstruction of the blood supply to the lower or upper extremities. PVD is known to affect 10% to 15% of the adult population in developed countries and is often associated with coronary artery disease.1 Arteriosclerosis obliterans (ASO) is the most common cause of PVD affecting the lower limbs. Peripheral ischemia can also result from various types of vasculitis, including thromboangiitis obliterans (TAO) or Buerger’s disease, which affects small- and medium-sized arteries and is related to tobacco use and male sex but not to other coronary risk factors. The 2 cardinal symptoms of limb ischemia are intermittent claudication and rest pain: the latter symptom occurs in patients with critical limb ischemia and coincides with ischemic ulceration and gangrene. The treatments of PVD include pharmacotherapy, percutaneous transluminal angioplasty, and vascular surgery and are chosen depending on the severity of the symptoms and the arteries involved.2 However, as many as 50% of patients with critical limb ischemia will undergo limb amputation within 1 year because of an insufficient response to the treatments.1,2
Recent progress in understanding the mechanisms underlying vascular formation in adults as well as during embryogenesis has opened up a therapeutic avenue for patients without any current options.3 Initial therapeutic approaches were aimed at delivering angiogenic factors, such as vascular endothelial growth factors (VEGF) and fibroblast growth factor-2, to ischemic tissues by using recombinant proteins or vectors encoding these factors.4,5 A number of preclinical studies reported improvement of perfusion by such methods in animal models of limb ischemia.6,7 Although the initial nonrandomized clinical trials showed beneficial effects, the results of controlled clinical trials have not been consistent.7 More recently, bone marrow–derived circulating endothelial progenitors have been identified in the peripheral blood8,9 and have been shown to contribute to both physiological and pathological angiogenesis in adults.10,11 These findings have led to the development of therapeutic neovascularization techniques using endothelial progenitors. Preclinical studies indicated that implantation of bone marrow mononuclear cells (BM-MNC), which contain endothelial progenitors, into ischemic limbs was very effective.12–14 Consequently, this therapeutic strategy was promptly tried for "no-option" patients with critical limb ischemia. The results of the first clinical trial showed that implantation of BM-MNC significantly improved the tissue oxygen concentration and blood flow in ischemic limbs, resulting in a decrease of rest pain and the involution of ischemic ulcers.15 Although promising results have been obtained, the mechanism by which cell therapy improves limb ischemia is largely unknown. Because direct incorporation of implanted cells into newly formed vessels is reported to be relatively rare, it has been assumed that angiogenic factors secreted by implanted cells are responsible for the efficacy of cell therapy.16,17
In the present study, we investigated the efficacy of cell therapy using peripheral blood mononuclear cells (PB-MNC) for the treatment of ischemic limbs. The results of our clinical trial showed that increased levels of angiogenic cytokines correlated with the response to treatment. Implantation of mononuclear cells increased the production of the angiogenic cytokines in muscle cells. A deficiency of the angiogenic cytokines in muscle cells blunted the ability of implanted cells to increase vascularization, suggesting that muscle cells but not mononuclear cells were important as a source of the angiogenic cytokines. Accordingly, we propose a novel mechanism whereby implanted cells promotes neovascularization in ischemic tissues.
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Materials and Methods |
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Animals
Generation and genotyping of interleukin (IL)-1ß–deficient mice have been previously described.18 C57BL/6 mice were purchased from SLC Japan. All mice used in this study were 8 to 12 weeks old. All experimental procedures were performed according to the guidelines of Chiba University for animal experiments and the protocols were approved by our institutional review board.
Collection of Mouse PB-MNC and BM-MNC
Donor mice were euthanized with a lethal dose of anesthetic, after which whole blood or bone marrow were harvested. Mononuclear cells were subsequently separated using Histopaque 1083 (Sigma). To deplete putative endothelial progenitors, the mononuclear cells were further incubated with a rat anti-mouse VEGF receptor-2 antibody (eBiosciences) at a concentration of 0.5 µg per 1 million cells. Then the population of cells negative for VEGF receptor-2 was obtained using a magnetic cell sorter (Miltenyi Biotec) according to the instructions of the manufacturer. The control cell population was prepared using an isotype control anti-rat IgG2a antibody. Sorted cells were washed twice with PBS and resuspended in PBS at a concentration of 1 million cells per 100 µL for the subsequent experiments. In all experiments, the viability of the mononuclear cells was more than 96.0%, as judged by Trypan blue dye exclusion.
Hindlimb Ischemia Model
After the mice were anesthetized, the proximal part of the femoral artery and the distal portion of the saphenous artery were ligated and stripped out after all side branches were dissected free. After 24 hours (designated as day 1), either mononuclear cells (1.0x106 cells in 100 µL of PBS) or PBS (100 µL) was injected into the ischemic muscle. As a rescue model, some of the IL-1ß–deficient mice were treated with PB-MNC on day 1 and given an intramuscular injection of 0.5 ng of mouse recombinant IL-1ß (IBL) on days 3, 5, and 7 after the operation. The mice were euthanized at the indicated times. Before death, hindlimb perfusion was measured with a laser Doppler perfusion analyzer (Moor Instruments).
Bone Marrow Transplantation Model
Before bone marrow transplantation, 8- to 10-week-old male wild-type or IL-1ß–deficient mice were exposed to total body irradiation (9 mGy). Bone marrow cell suspensions were isolated by flushing the femurs and tibias harvested from wild-type or IL-1ß–deficient mice. Bone marrow cell suspensions (1.5x107 cells) were injected intravenously via the tail vein within 6 hours of irradiation. The chimeric rate was more than 95%, as determined by fluorescence-activated cell sorting analysis of chimeric mice transplanted with bone marrow cells from the green fluorescent protein (GFP) transgenic mice.
Histology
Vastus and rectus femolis muscle tissues were removed from the ischemic limbs after systemic perfusion with PBS and immediately embedded in OCT compound (Sakura Finetechnical). Then each specimen was snap frozen in liquid nitrogen and cut into 6-µm sections. The sections were stained with antibodies for myosin (MF-20), CD31 (Pharmingen), or IL-1ß (Santa Cruz Biotechnology) and counterstained with hematoxylin or 4',6-diamidino-2-phenylindole (DAPI). Two transverse sections of the entire muscle were photographed digitally at a magnification of x100 (12 to 16 photographs per mouse), and these photographs were reviewed in a blinded manner. Capillary endothelial cells were identified by immunoreactivity for CD31 and quantified as the number per square millimeter.
Cell Culture
C2C12 myoblasts were cultured as described previously.19 Briefly, cells were maintained in DMEM supplemented with 20% FBS (growth medium) until use. In all experiments, the cells were seeded into 60-mm or 100-mm plastic culture dishes at a concentration of 5x103 cells/cm2 (day 0) and were incubated at 37°C in a mixture of 95% air and 5% CO2. After 24 hours (day 1), the growth medium was changed to DMEM supplemented with 2% horse serum (differentiation medium). On day 4, the medium was replaced by fresh differentiation medium with or without PB-MNC. On day 5, cells were harvested after the mononuclear cells were completely removed by washing 5 times with PBS.
Statistical Analysis
Data are shown as mean±SEM unless otherwise noted. Changes of the rest pain scale and walking distance over time were analyzed by the rank sum test. Differences of patient background factors between responders and nonresponders were analyzed with the 
2 test or Fisher’s exact test. Comparison between multiple groups was performed by 1-way ANOVA followed by the Bonferroni procedure for comparison of mean values. Comparisons between two groups were done with the two-tailed Student’s t test or 2-way ANOVA. For these analyses, of P<0.05 was considered statistically significant.
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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Therapeutic Neovascularization Using PB-MNC for Critical Limb Ischemia
Because most patients with critical limb ischemia have concomitant coronary artery disease and cerebrovascular disease, the collection of bone marrow cells, which requires general anesthesia,15 could cause fatal events in such patients. Given that angiogenic factors secreted from BM-MNC play a major role in cell therapy, PB-MNC may be more beneficial because collection of PB-MNC is much safer and less expensive. To examine the effects implanting PB-MNC, we produced a model of hindlimb ischemia in C57BL/6 mice and implanted PB-MNC into the ischemic limbs of these animals. Implantation of PB-MNC significantly increased perfusion compared with that in the control group (PBS) as assessed by laser Doppler analysis (Figure 1A). The capillary density in ischemic limbs was significantly greater in the PB-MNC group than in the PBS group (Figure 1B). Although BM-MNC has been reported to contain much more (
100-fold) endothelial progenitors than PB-MNC, there was no significant difference of neovascularization between the PB-MNC group and the BM-MNC group (Figure 1A and 1B), indicating that implantation of PB-MNC is as efficient as BM-MNC for the treatment of limb ischemia and suggesting that endothelial progenitors do not play a pivotal role in the treatment of limb ischemia at least by PB-MNC.
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After obtaining approval from the ethical committee of Chiba University Graduate School of Medicine, we started a pilot clinical trial to investigate whether therapeutic neovascularization by implantation of PB-MNC is feasible and effective for ischemic limbs. We enrolled 29 patients with critical limb ischemia caused by ASO or TAO who had no treatment options. More than 80% of the patients were recommended to undergo major amputation by their doctors before enrollment because of unhealed ischemic ulcers or gangrene despite conventional therapy (Tables 1 and 2
). Approximately half of the patients had chronic renal failure and were on dialysis 3 times weekly (Table 1). Apart from 5 TAO subjects, most of the patients (82.7%) had 1 or more complications (Table 1). We implanted PB-MNC into the ischemic limbs of these patients twice within a 1-month period and estimated their response at 2 months, 6 months, and 1 year after treatment (as described in the online data supplement). Rest pain was significantly decreased and was nearly normalized by 1 year after treatment (Figure 1C). The maximum walking distance also improved significantly, and this improvement was preserved for a year (Figure 1D). Three patients (11.1%) underwent major amputation, which was much less frequent compared with the reported annual rate of amputation in patients with critical limb ischemia (50%).2 Improvement of ischemic ulcers was observed 16 of 24 patients (66.7%) (Figure 1E), whereas only 31% of the patients showed substantial improvement of the ankle–brachial pressure index (ABPI), presumably because of underestimation of improvement in this index of hemodialysis patients. There were no major complications related to the treatment, such as death or coronary events. Three patients died of unrelated causes, including pneumonia and chronic renal failure (11.1%), which was lower than the reported annual mortality rate of patients with critical limb ischemia (25%).1 These results indicate that implantation of PB-MNC was a safe and effective treatment for critical limb ischemia.
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Factors Associated With the Response to Treatment
We next investigated the factors related to the response to treatment. We divided the patients into a group of responders (n=21) and a group of nonresponders (n=8) according to a response score estimated from the improvement of rest pain, ischemic ulcers, walking distance, and ABPI. Then we compared their background factors and laboratory data. There were no significant differences of patient background factors, including age, gender, and coronary risk factors, between responders and nonresponders (Table 2). The serum level of C-reactive protein, a marker of inflammation induced by cytokines, was significantly higher in the responders after implantation (Table 2). Therefore, we examined the plasma levels of various angiogenic cytokines in the patients at days 1, 3, 7, and 14 after implantation. We found that the peak levels of IL-1ß, IL-6, and VEGF, but not tumor necrosis factor-
or granulocyte colony-stimulating factor, were markedly higher in responders than in nonresponders (Figure 2A; Figure I in the online data supplement). In contrast, there were no significant differences of the number of implanted mononuclear cells and CD34-positive cells between the 2 groups (Figure 2A). Consistent with these results, deprivation of putative endothelial progenitors (VEGF receptor-2–positive cells) did not affect the ability of implanted mononuclear cells to promote neovascularization in a mouse model of hindlimb ischemia (Figure 2B). Thus, we speculated that the increase of angiogenic factors secreted by implanted mononuclear cells might influence the efficacy of this therapy.
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Increased Expression of IL-1ß in Ischemic Limbs Is Crucial for Neovascularization
Because IL-1ß is known to be a potent angiogenic cytokine and induces a number of angiogenic factors including VEGF,20,21 we examined the role of IL-1ß on neovascularization induced by mononuclear cell implantation in a model of hindlimb ischemia. When PB-MNC from wild-type mice were implanted into the ischemic limbs of wild-type mice, blood flow and capillary density were significantly increased compared with those in a PBS-treated group (Figure 3A and 3B). Unexpectedly, PB-MNC derived from IL-1ß–deficient mice18 increased the blood flow of the ischemic limbs in wild-type mice as efficiently as wild-type PB-MNC (Figure 3A). Likewise, implantation of IL-1ß–deficient PB-MNC significantly increased capillary density compared with the PBS-treated group (Figure 3B). In contrast, implantation of wild-type PB-MNC into ischemic limbs of IL-1ß–deficient mice had no effect on neovascularization (Figure 3A and 3B), suggesting that increased expression of IL-1ß in ischemic limbs is more important for neovascularization than expression by implanted cells. Expression of VEGF in the ischemic limbs of wild-type mice was significantly elevated by implantation of IL-1ß–deficient PB-MNC as well as wild-type PB-MNC compared with the PBS-treated group (Figure 3C). However, implantation of wild-type PB-MNC failed to induce VEGF expression in the ischemic limbs of IL-1ß–deficient mice (Figure 3C). The pattern of IL-1ß expression in ischemic limbs was very similar to that of VEGF (Figure 3D). A significant increase of IL-1ß expression was observed in the ischemic limbs of wild-type mice treated with wild-type or IL-1ß–deficient PB-MNC, whereas there was no induction of IL-1ß in the ischemic limbs of IL-1ß–deficient mice after implantation of wild-type PB-MNC (Figure 3D). These results suggest that implantation of PB-MNC induces IL-1ß expression in ischemic limbs and promotes neovascularization by the induction of angiogenic factors such as VEGF.
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Wild), wild-type PB-MNC (WildPrevious studies demonstrated that infiltration of macrophages plays a critical role in IL-1ß–induced neovascularization.22,23 To test this, we injected PB-MNC from GFP transgenic mice into the ischemic limbs of wild-type or IL-1ß–deficient mice and performed histological analyses at 5 days after treatment. The number of infiltrating host-derived (GFP-negative) macrophages was significantly fewer in the ischemic limbs of IL-1ß–deficient mice than in those of wild-type mice (supplemental Figure II). PB-MNC implantation significantly induced macrophage infiltration compared with PBS-treated mice (supplemental Figure II). There was no difference in infiltration of macrophages into nonischemic limbs between wild-type and IL-1ß–deficient mice (supplemental Figure II). Thus, infiltration of macrophages may be also involved in the mechanisms underlying IL-1ß-induced neovascularization.
To investigate whether host-derived hematopoietic cells contribute to induction of IL-1ß by mononuclear cell implantation, we produced chimeric mice. When PB-MNC from IL-1ß–deficient mice were implanted into the ischemic limbs of wild-type mice with IL-1ß–deficient bone marrow, blood flow and capillary density were significantly increased compared with those in a PBS-treated group (Figure 3E and 3F). In contrast, injection of IL-1ß–deficient PB-MNC into the ischemic limbs of IL-1ß–deficient mice with wild-type bone marrow did not enhance neovascularization (Figure 3A, 3B, 3E, and 3F). Consistent with these results, PB-MNC implantation markedly induced IL-1ß expression in the ischemic limbs of wild-type mice with IL-1ß–deficient bone marrow compared with the limbs of IL-1ß–deficient mice with wild-type bone marrow (Figure 3G), which suggests a minor role of host-derived hematopoietic cells in the production of IL-1ß after treatment.
Critical Roles of Muscle-Secreted Angiogenic Factors
To determine the type of cells in which IL-1ß expression is induced by implantation of PB-MNC, we performed immunohistochemical analysis of ischemic limbs after implantation. Expression of IL-1ß was localized to the skeletal muscle cells, as identified by staining for sarcomeric myosin, and was particularly detected in the regenerating tissues (Figure 4A). Likewise, in situ hybridization revealed that IL-1ß was predominantly expressed by muscle cells and, to a lesser extent, by other types of cells such as vascular cells and infiltrating leukocytes (Figure 4B and data not shown). To test whether PB-MNC could increase the expression of angiogenic cytokines by muscle cells, we coincubated mouse embryonic muscle cells (C2C12) with PB-MNC from wild-type mice for 24 hours under differentiating conditions and harvested muscle cells after intensive wash with PBS to eliminate PB-MNC from the samples. Coincubation with PB-MNC increased the expression of various angiogenic cytokines such as IL-1ß, IL-6, and VEGF by C2C12 cells (Figure 4C). C2C12 cells treated with PB-MNC as well as nontreated cells expressed myosin (Figure 4D), whereas expression of CD31 was not detected in these cells (Figure 4C), indicating that contamination of PB-MNC was negligible. Coincubation of C2C12 cells with human PB-MNC also induced expression of mouse cytokines as determined by RPA using a mouse-specific probe (supplemental Figure III). We, therefore, concluded that implantation of mononuclear cells promotes neovascularization by stimulating muscle cells to increase the production of angiogenic cytokines such as IL-1ß.
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We then examined whether treatment with IL-1ß restores the efficacy of PB-MNC implantation in the ischemic limbs of IL-1ß–deficient mice. We observed that neovascularization occurred in the ischemic tissues at 1 week and that the appearance of the skeletal muscles became normal by 3 weeks after implantation (Figure 4E). Implantation of wild-type PB-MNC did not induce neovascularization in the ischemic limbs of IL-1ß–deficient mice at 1 week, and, thus, necrosis occurred by 3 weeks after implantation (Figure 4E). In contrast, administration of IL-1ß in conjunction with implantation of wild-type PB-MNC significantly increased neovascularization (P<0.01 versus IL-1ß–deficient mice treated with wild-type PB-MNC; n=3) and prevented necrosis of the ischemic limbs in IL-1ß–deficient mice at 3 weeks (Figure 4E). Consistent with the results of histological analyses, improvement of blood flow by PB-MNC implantation in wild-type mice was significantly better than in IL-1ß–deficient mice (Figure 3A and supplemental Figure IV). Moreover, administration of IL-1ß in conjunction with implantation of wild-type PB-MNC partially improved the effect of PB-MNC implantation on blood flow in IL-1ß–deficient mice (supplemental Figure IV). However, administration of IL-1ß without PB-MNC implantation did not improve limb ischemia in wild-type mice (supplemental Figure V). Thus, it is conceivable that induction of IL-1ß is prerequisite for the efficacy of PB-MNC implantation, but an IL-1ß only treatment is insufficient for limb salvage.
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Discussion |
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The present study provided a possible mechanism for the process of neovascularization during cell therapy for limb ischemia. The results of our clinical trial showed that angiogenic cytokines, especially IL-1ß, were associated with the response to treatment. Many previous studies have suggested that angiogenic factors secreted by implanted cells play a critical role in therapeutic neovascularization.16,17 In contrast, our in vitro and in vivo studies demonstrated that the implanted mononuclear cells did not secrete cytokines sufficient for neovascularization but, instead, stimulated muscle cells to produce IL-1ß. This is consistent with our observation that most of the implanted cells disappeared from the ischemic tissues as early as 3 days after implantation, which was before reconstruction of the vascular system started (K.T., T.M., I.K., unpublished data, 2006). Thus, it is likely that muscle cells but not implanted cells are a major source of angiogenic cytokines in ischemic limbs.
We noted that IL-1ß was predominantly expressed by myocytes with central nuclei in ischemic limbs, indicating that these cells are regenerating myocytes (Figure 4A). We also observed that implantation of mononuclear cells increased the number of central nucleated myocytes in ischemic limbs (K.T., T.M., I.K., unpublished data, 2006). We therefore propose a novel model of neovascularization, in which implanted mononuclear cells enhance muscle regeneration and the increased expression of IL-1ß by regenerating myocytes promotes neovascularization via induction of angiogenic factors, thereby contributing to limb salvage. Implantation of wild-type mononuclear cells increased the number of regenerating myocytes in the ischemic limbs of IL-1ß–deficient mice compared with PBS-treated IL-1ß–deficient mice (Figure 4E and supplemental Figure VI). However, the regeneration of myocytes was not accompanied by neovascularization at 1 week, and, thus, necrosis occurred by 3 weeks after implantation (Figure 4E). These results suggest that implantation of mononuclear cells promotes muscle regeneration and that the regenerated muscle-secreted IL-1ß induces neovascularization, leading to suitable conditions for further muscle regeneration. Thus, although expression of IL-1ß by muscle cells is required for mononuclear cells promoting neovascularization, administration of IL-1ß could not obviate the need for injection of mononuclear cells.
We recently reported a similar finding that granulocyte colony-stimulating factor acts directly on cardiomyocytes and promotes neovascularization in ischemic myocardium by inducing the production of angiogenic factors.24 Our results also coincide with recent evidence suggesting an important role for the interaction between macrophages and skeletal muscle in the process of muscle regeneration after injury.25 During this process, muscle cells modulate macrophage invasion by releasing cytokines such as monocyte chemoattractant protein-1 and VEGF.26 On the other hand, macrophages release factors in vitro that promote the proliferation of muscle cells.27 Macrophages are also present in vivo at sites where muscle regeneration occurs,28 and macrophage depletion significantly impairs muscle regeneration after transplantation of myogenic cells,29 suggesting a critical role of macrophages in muscle repair. However, there are no definitive studies to show which factors (if any) are released by macrophages in vivo to influence the process of muscle repair. In our study, it is unclear how the implanted mononuclear cells stimulated muscle cells to proliferate and induce the expression of angiogenic factors. It would be also interesting to determine whether the similar mechanisms are involved in other modes of therapeutic vascularization such as cytokine therapy. Further studies on the roles of cellular communications will allow us to develop more effective treatments for ischemic vascular disease.
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Acknowledgments |
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This work was supported by a grant-in-aid for scientific research and developmental scientific research from the Ministry of Education, Science, Sports, and Culture, Health and Labor Sciences Research Grants (to I.K.) and grants from the Japan Research Foundation for Clinical Pharmacology, NOVARTIS foundation, and the Ministry of Education, Science, Sports, and Culture of Japan (to T.M.).
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Footnotes |
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*Both authors contributed equally to this study.
Original received November 1, 2005; revision received March 9, 2006; accepted March 22, 2006.
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