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Ann Thorac Surg 2002;73:1210-1215
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Therapeutic angiogenesis induced by local autologous bone marrow cell implantation

Kimikazu Hamano, MD*a, Tao-Sheng Li, MDa, Toshiro Kobayashi, MDa, Ken Hirata, MDa, Masafumi Yano, MDa, Michihiro Kohno, MDa, Masunori Matsuzaki, MDa

a First Department of Surgery and Second Department of Internal Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan

Accepted for publication December 17, 2001.

* Address reprint requests to Dr Hamano, First Department of Surgery, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan 755-8505
e-mail: kimikazu{at}po.cc.yamaguchi-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Therapeutic angiogenesis was induced by local autologous bone marrow cell implantation (BMCI) in ischemic hindlimb or ischemic heart models in rats. This study was designed to investigate the toxicity and therapeutic potency of local BMCI using a chronic coronary occlusion model in dogs.

Methods. The canine chronic coronary occlusion model was created by ligating of the left anterior descending artery (LAD). The myocardium in the left ventricle was divided into distinct normal, marginal, and infarction areas 30 days after LAD ligation. Each area was injected at two locations, with either 2 x 107 bone marrow cells (n = 7, BMCI group) or 0.1 mL phosphate-buffered saline (PBS) only (n = 7, PBS group), respectively. Hemodynamics were evaluated by a single ultrasonic transducer and echocardiography before and 30 days after the treatment. Angiogenesis was evaluated by vessel count 30 days after the treatment. The toxicity of BMCI treatment was also evaluated in 8 normal dogs by following changes in electrocardiography (ECG), echocardiography, local histology, and systemic biochemistry indexes.

Results. There was a significantly higher percentage of wall thickening in the marginal area in the BMCI group than in the PBS group 30 days after treatment (14.5 ± 2.28 versus 8.1 ± 3.00, p = 0.002). Significantly more microvessels were observed in the marginal area in the BMCI group than in the PBS group 30 days after treatment (127.7 ± 20.1 versus 88.0 ± 10.2/field, p = 0.0007). No systemic or local toxicity was found following BMCI treatment in the acute or chronic phases.

Conclusions. BMCI treatment improved local wall thickening dynamics, presumably due to the angiogenesis induced by the treatment. This indicates that it might be a safe and effective therapy for ischemic heart disease.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Therapeutic angiogenesis has been successfully induced in experimental animal models and human clinical trials by various methods such as the intramyocardial application of angiogenic cytokines [1–4], gene transfer of angiogenic cytokines [5–7], and transmyocardial laser revascularization [8, 9]. However, few clinical trials of therapeutic angiogenesis have been carried out because of the unstable effect, difficult technique, and the risk of systemic or local toxicity.

We have already reported that local autologous bone marrow cell implantation (BMCI) was able to induce effective angiogenesis and improve physiologic function in rat models of ischemic hearts and hindlimbs [10–12]. The angiogenic potency of bone marrow cells was found to be related to the secretion of various angiogenic growth factors and cytokines [13] and the endothelial differentiation from the endothelial progenitors in bone marrow cells [14–17]. It seemed that this treatment would be a cost-effective and simple method of inducing therapeutic angiogenesis to treat ischemic disease.

Before further promoting BMCI treatment in a clinical trial, we investigated the therapeutic potency of BMCI using a canine chronic coronary occlusion model and clarified the local and systemic toxicity of this treatment in normal dogs.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Animals
A total of 22 dogs weighing 9 to 12 kg were used for these experiments. Animals were obtained from Japan SLC Inc (Hamamatsu, Japan) and housed at the Institute of Laboratory Animals, Yamaguchi University School of Medicine. All experiments were approved by the institutional Animal Care and Use Committee of Yamaguchi University School of Medicine.

Canine chronic coronary occlusion model
The animals (n = 14) were anesthetized with an intramuscular injection of ketamine hydrochloride (20 mg/kg) and intravenous sodium pentobarbiturate (30 mg/kg), then ventilated mechanically with a volume ventilator. A right thoracotomy was performed through the fourth intercostal space. Acute myocardial infarction was caused by ligation of the left anterior descending artery (LAD) and all diagonal branches and distal sites of the oblique marginal branches. The chest and thoracotomy incisions were closed.

Local bone marrow cell implantation
Animals were randomized into two groups and anesthetized as described 30 days after LAD ligation. Autologous bone marrow cells were collected from the iliac bone and mixed with heparinized phosphate-buffered saline (PBS) using a sterile technique. Density centrifugation using Mono-poly resolving medium (Dainippon-seiyaku Co, Ltd, Japan) was carried out to remove erythrocytes according to the instructions of the manufacturer. BMCs were suspended with PBS at a density of 2 x 108/mL for injection. A left thoracotomy was performed through the fourth intercostal space. Myocardial infarction of the left ventricle was seen in all the animals. The left ventricle was exposed and divided into the infarction area (anterior wall), marginal area (lateral wall), and normal area (posterior wall) as shown in Figure 1. Two points in each area were injected with 2 x 107 BMCs in 0.1 mL PBS (n = 7, BMCI group) or 0.1 mL PBS only (n = 7, PBS group) into the myocardium of a depth of about 2 mm using a 26-gauge needle.



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  		Fig 1. Experimental canine chronic coronary occlusion model (A) and the schedule of treatments (B). The canine chronic coronary occlusion model was made by ligating the left anterior descending artery (LAD) and all the diagonal branches and distal sites of the oblique marginal branches. Shown are (a) the attached positions of a single crystal in the normal area, (b) the marginal area, and (c) the infarction area. Black dots indicate the injection sites of bone marrow implantation. (Cx = circumflex artery; BMCs = bone marrow cells; PBS = phosphate-buffered saline; %WT = percent wall thickening; Echo = echocardiography.)

 
Hemodynamic studies
The cardiac function and local wall motion were evaluated before and 30 days after the BMC or PBS injection. The single ultrasonic transducer (Wall Tracker Module, WT-10; Sonometrics Corporation, Ontario, Canada), which was attached and sutured to the infarction, marginal, and normal areas (Fig 1) in the left ventricular wall [18, 19], was used to measure the wall thickening dynamics in each area. Parasternal two-dimensional echocardiographs were recorded to evaluate the cardiac function and local wall motion using the following indexes: left atrial diameter (LAD), left ventricular end-systolic diameter (LVSD), left ventricular diastolic diameter (LVDD), and percent fractional shortening (%FS).

All the animals were killed 30 days after the injection of BMCs or PBS. The hearts were extracted and samples of myocardium from the infarction, marginal, and normal areas were collected and embedded in Tissue-Tek O.C.T. compound. Tissues were snap frozen in liquid nitrogen for histologic examination.

Histologic evaluation for angiogenesis
Tissue slices 5-µm thick were fixed and blocked, then incubated overnight at 4°C with the primary mouse antidog CD34 monoclonal antibody, donated by Dr P. A. McSweeney [20]. Positive staining was detected by sequentially incubating with biotin-labeled secondary antibody and avidin-biotin peroxidase complex in the LSAB 2 Kit (Dako, Carpinteria, CA) sequentially, according to the protocol of the manufacturer. The sections were washed three times with PBS before each incubation. Counterstaining was performed with methyl green. Angiogenesis was assessed by microvessel counting under light microscopy. The microvessels in the normal, marginal, and infarction areas were examined under x200 microscopy by a single observer who was blinded to the treatment groups and the mean number of vessels in each high-power field was used for statistical analysis.

Systemic and local toxicity of local bone marrow cell implantation
Eight healthy dogs were used to investigate the systemic and local toxicity of BMCI treatment. The dogs were randomly divided into two groups (n = 4 in each group) and injected at six points with BMCs or PBS in the LAD area as described above. The ECG and echocardiographs were recorded 1, 3, 7, 30, and 240 days after the treatment. Samples of serum were also collected at the same time points for the measurement of white blood cells (WBC), alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), creatinine kinase (CK), and CK-MB. The dogs were killed 240 days after the treatment and the local myocardium was collected for histologic examination.

Statistical analysis
All data are expressed as mean ± the standard deviation. Statistical significance was evaluated by the unpaired Student’s t test for comparisons between two means; by analysis of variance (ANOVA) followed by Scheffe’s procedure for more than two means; and by repeated ANOVA to test for interaction. Data were considered significant when the p value was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Improvement in left ventricular wall motion by local bone marrow cell implantation
The degrees of local wall thickening (%WT) in each area after the BMCI treatment are shown in Figure 2. The %WT in the normal area did not change with time and no significant difference was observed between the two groups at any time point. The %WT in the marginal area increased with time in the BMCI group but decreased in the PBS group. The different changes of %WT after the injection of bone marrow cells or PBS resulted in a significantly higher %WT in the BMCI group than in the PBS group 30 days after treatment (14.5 ± 2.28 versus 8.1 ± 3.00, p = 0.002). The %WT in the area of infarction decreased with time in both groups and no significant difference was found between the two groups.



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  		Fig 2. Changes in local cardiac wall motion in the normal area (left), the marginal area (middle), and the infarction area (right) after bone marrow cell implantation. Representative recording of wall thickening measured by ultrasonic transducer (upper and middle panel). The percent wall thickening (lower panel) was calculated by systolic thickening divided by end-diastolic thickness. In the marginal area, the percent wall thickening was significantly greater in the BMCI group than in the PBS group. (BMCI = bone marrow cell implantation group; PBS = phosphate-buffered saline injection group; Pre = before injection; Post = 30 days after injection, %WT = percent wall thickening.)

 
The data of heart rate, LAD, LVSD, LVDD, and %FS are summarized in Table 1. No significant differences were seen between the two groups at any time point.


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  		Table 1. Hemodynamics Measured by Echocardiographic Study

 
Induction of angiogenesis by local bone marrow cell implantation
The result of immunohistochemical staining with canine anti-CD34 antibody is shown in Figure 3. The density of the microvessels was significantly higher in the BMCI group than in the PBS group in the marginal area 30 days after the treatment (127.7 ± 20.1 versus 88.0 ± 10.2, p = 0.007). However, the density of microvessels in the normal and infarction areas was not significantly different between the two groups.



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  		Fig 3. Immunohistochemical staining with canine anti-CD34 in (A) the phosphate-buffered saline injection (PBS) group and (B) the bone marrow cell implantation (BMCI) group in the marginal area. (C) Quantitative analysis of the microvessel density in each area showed that the density of microvessels in the marginal area was significantly higher in the BMCI group than in the PBS group.

 
No significant systemic or local toxicity after local bone marrow cell implantation
There were no significant differences in the levels of WBC, alanine aminotransferase, aspartate aminotransferase, Creatinine, BUN, LDH, CK, and CK-MB between the BMCI and PBS groups throughout the experimental period. No significant changes in ECGs, which were recorded for 1 hour continuously at each time point, were seen in any of the animals. There was no significant difference in cardiac function or local wall motion between the BMCI and PBS groups according to echocardiographic examination at each time point. Fibrotic change was seen in the myocardium of both groups but it was localized only at the site of injection and was less than 1% in area. No other significant histologic changes such as calcification, blood cell production, or inflammatory cell migrations were observed in the hematoxilin-eosin stained specimens from the myocardium 240 days after BMCI treatment.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Surgical coronary artery bypass grafting (CABG) or percutaneous catheter intervention (PCI) has become an effective treatment for ischemic heart disease. In some patients, however, all or parts of the ischemic area are unsuitable for surgical CABG or PCI due to technical problems related to surgery or catheter intervention. As therapeutic angiogenesis can be effectively induced by the local implantation of autologous bone marrow cells [10–13], it might be an effective method for treating these patients, either by itself or combined with surgical CABG or PCI. In a preclinical study for assessing the use of this treatment in ischemic heart disease, we investigated whether the local implantation of bone marrow cells would induce angiogenesis and improve cardiac function in a chronic coronary occlusion model in dogs.

Some researchers have successfully induced angiogenesis by the intracoronary or intramyocardial administration of basic fibroblast growth factor using an acute myocardial infarction model in dogs, which resulted in a reduction in the infarction size and improvement in cardiac function [3, 4]. The local implantation of autologous bone marrow cells to induce angiogenesis should be easy to perform because of its lower risk, low toxicity, and cost-effectiveness. In the present experiment, local bone marrow implantation was performed 30 days after LAD ligation. We selected a chronic coronary occlusion model because we plan to apply this treatment alone or combined with CABG to patients with chronic ischemic heart disease.

In this chronic coronary occlusion model, the %WT in the marginal area increased with time after treatment with local bone marrow cell implantation but decreased after the PBS injection. This indicates that the wall thickening dynamics were significantly improved by local bone marrow cell implantation. The improved wall thickening dynamics by local bone marrow cell implantation were only observed in the marginal area and not in the normal and infarction areas in this chronic coronary occlusion model. In accordance with the wall thickening dynamics, a significantly higher density of microvessels was also observed in the BMCI group compared with the PBS group but only in the marginal area. Although we have not measured the regional blood perfusion, the newly formed vessels resulting from this treatment might provide sufficient blood supply for the beating of the hibernating myocardium [21]; the enhanced %WT in the marginal area might be attributable to the increased density of the microvessels. The above view is supported by the fact that a higher density of microvessels was only observed in the marginal area and not in the normal or infarction areas in the present study. Of course, the improvement of %WT in the marginal area could be partly due to the differentiation of myocytes from the implanted bone marrow cells [22] or to some other unknown mechanism.

Differing from the investigation by Kimihata and colleagues in an acute-phase LAD ligation model [23], the echocardiographic data in this study showed no significant improvement in hemodynamics after the treatment with local bone marrow cell implantation. Possibly the cell numbers and sites of implantation in this study were insufficient to improve the total cardiac function. The characteristics of the chronic coronary occlusion model used in this study should also be taken into consideration; in other words, the improvement in the wall thickening dynamics was so limited only in the marginal area that it was insufficient to improve global function.

Our investigation of the safety of local autologous BMCI in healthy dogs revealed no evidence of any systemic or local toxicity in the acute or chronic phases. Moreover, histologic evaluation of hematoxylin-eosin stained specimens revealed no calcification, blood cell production, or local inflammatory responses such as neutrophil or lymphocyte migration 240 days after local BMCI treatment. The minimum fibrosis in the normal myocardium was localized at the site of injection and was considered a result of myocardial injury due to the injection procedure itself.

The improvement in cardiac function after BMCI treatment was limited to the increase of wall thickening dynamics in this study and the effectiveness of this treatment needs further clarification. The appropriate cell number and injection point also need to be further investigated. The evaluation of the safety of BMCI treatment in this study was based on a small number of animals, limited cell number and implantation points, a small item of measurement, and a limited observation period. Although further investigation into the safety and the therapeutic potency of this treatment is required, the advantages of this treatment lie in its simplicity and cost- effectiveness in a clinical trial.

Based on the results of the present study we conclude that local autologous BMCI is a simple and, it is hoped, safe and effective treatment for ischemic heart disease. With further improvement in the near future, this treatment should be beneficial for patients who have refractory ischemic heart diseases but are unsuitable candidates for the traditional treatments of CABG and PCI.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by the Research Fund for the Development of New Medical Treatment of the Ministry of Education and Japan Heart Foundation and by a Pfizer Pharmaceuticals grant for research on coronary artery disease.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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