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J Thorac Cardiovasc Surg 2002;123:1132-1140
© 2002 The American Association for Thoracic Surgery
Evolving Technology (ET) |
From the Toronto General Research Institute, Division of Cardiovascular Surgery, and Division of Clinical Biochemistry, University Health Network, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Supported by research grants to R.K.L. from the Medical Research Council of Canada (MT-13665). R.K.L. is a Career Investigator of the Heart and Stroke Foundation of Ontario.
Received for publication July 11, 2001. Revisions requested Aug 3, 2001; revisions received Aug 31, 2001. Accepted for publication Sept 18, 2001. Address for reprints: Ren-Ke Li, MD, Toronto General Hospital, CCRW 1-815, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4 (E-mail: RenKeLi{at}uhnres.utoronto.ca).
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Abstract |
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Introduction |
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Adult bone marrow contains stromal cells, which can differentiate into myogenic
1 and endothelial 2 progenitor cells. These stromal cells should be ideal to induce both myogenesis and angiogenesis when transplanted after a myocardial infarction. It has been reported that marrow stromal cells implanted into an infarct region differentiated to a fibroblast phenotype, whereas stromal cells implanted into normal myocardium differentiated toward a cardiomyocyte appearance. 3,4 In a previous study we found that both fresh and cultured bone marrow stromal cells induced angiogenesis when transplanted into a cryoinjured region in rats. 5 However, only stromal cells treated before transplantation with 5-azacytidine to induce a myogenic phenotype contributed to myogenesis and improved heart function by preventing scar thinning and chamber dilatation. We therefore transplanted adult bone marrow stromal cells that had been treated with 5-azacytidine into infarcted myocardium in a porcine model to investigate the survival of the transplanted stromal cells in the myocardial infarct region, the differentiation of these cells into heart cells and blood vessel cells, and the effects of the implanted cells on regional perfusion, wall motion, and global heart function. We found that the transplanted stromal cells survived and formed new cardiac tissue and capillaries. Myocardial regional perfusion was improved and contractile function was preserved after transplantation.
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Methods |
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The animals were medicated in advance with ketamine hydrochloride (20 mg/kg intramuscularly). Anesthesia was induced with a ventilation mask with 4% to 5% isoflurane and oxygen at 2 to 3 L/min. The animals were intubated with a cuffed endotracheal tube and ventilated with 100% oxygen to maintain PaCO2 between 35 and 45 mm Hg. Anesthesia was maintained with 1% to 2.5% isoflurane in oxygen at a flow rate of 2 to 3 L/min and inspired oxygen fraction of 100%. Electrocardiography was used to monitor heart rate, rhythm, and ST-segment changes during the surgical procedure.
Cell isolation and preparation
With the animal under general anesthesia, 10 mL sternal bone marrow was aspirated with a bone marrow aspirate needle and then cultured in cell culture medium (Iscove modified Dulbecco medium with 20% fetal bovine serum, 100-U/mL penicillin G, 100-µg/mL streptomycin, and 0.2-µg/mL amphotericin B). The cells were incubated with 95% air and 5% carbon dioxide at 37°C.
5-Azacytidine induction of stromal cells to a myogenic phenotype
Forty-eight hours after the initiation of the culture, 5-azacytidine was added into the culture medium at a final concentration of 10 mmol/L. The medium was changed 24 hours later, and the cells were continually cultured for 4 weeks with medium changed every 2 to 3 days. Because hematopoietic stem cells do not attach onto the culture dish, they were removed with the culture medium changes. The cells were subcultured to 60% confluency. The cells were similarly incubated with 5-azacytidine 1 day before transplantation.
Cell labeling with bromodeoxyuridine
To discriminate the transplanted cells in the recipient myocardium, 30% of the transplanted cells were labeled with bromodeoxyuridine (BrdU) as previously described elsewhere. 6 Briefly, 74 µL of a 0.4% BrdU solution was added into each culture dish with 30 mL of culture medium 2 days before transplantation and incubated with the cells for 24 hours.
Cell preparation for transplantation
The stromal cells were dissociated from the culture dish with 0.05% trypsin in phosphate-buffered saline solution (PBS), collected, and centrifuged at 570g. The cells were suspended with culture medium to obtain a concentration of 100 x 106 cells in 1.5 mL. The cell suspension was aspirated into two tuberculin syringes.
Immunohistochemical staining
Cultured bone marrow stromal cells were washed with PBS and fixed with methanol at -20°C for 20 minutes. After being washed with PBS three times, the cells were incubated with the monoclonal antibodies against cardiac-specific troponin I (Spectral Diagnostics Inc, Toronto, Ontario, Canada), CD34 (Vector Laboratories Inc, Toronto, Ontario, Canada), desmin (DAKO Diagnostics Canada, Inc, Toronto, Ontario, Canada), 
-smooth muscle actin (Sigma Aldrich, Toronto, Ontario, Canada), and vimentin (American Research Products, Toronto, Ontario, Canada) at 37°C for 45 minutes. The cells in the control group were incubated with PBS without antibodies. After incubation the cells were washed three times (15 minutes each) with PBS and then incubated with secondary antibodies conjugated with peroxidase at 37°C for 45 minutes. The samples were washed three times with PBS and then immersed in diaminobenzidine and hydrogen peroxide solution (2-mg/mL diaminobenzidine and 0.03% hydrogen peroxide in 0.02 mL/L phosphate buffer) solution for 15 minutes. The samples were coverslipped and photographed.
The positively and negatively staining cells in two dishes for each transplant were counted at 200 times magnification. Five high-power fields in each culture dish were randomly selected and the positively and negatively staining cells in each field were counted and averaged. The results were expressed as percentage of positive cells.
Myocardial infarction
With the animal under general anesthesia the right carotid artery was exposed and a coil (10 x 1 mm; Target; Boston Scientific Corp, Natick, Mass) was lodged in the distal third of the left anterior descending coronary artery and in the origin of the second diagonal artery with a catheter. 6 A piece of Gelfoam sponge (1 x 1 x 10 mm; Upjohn Company of Canada, Dons Mills, Ontario, Canada) was placed into each coil to ensure complete occlusion of the arteries. The surgical incision was closed. Blood pressure, heart rate, and electrocardiographic data were monitored during the procedure and for 3 hours afterward. Severe ventricular arrhythmias appearing during this time were treated by intravenous administration of lidocaine. Numorphan (5.0 mg every hour for 6 hours after operation) was administered intramuscularly for pain control. Antibiotics were given as necessary.
Autologous cell transplantation
With the animal under general anesthesia the infarct region was exposed through a left thoracotomy 4 weeks after the myocardial infarction. 6 The animals were randomly assigned into transplant and control groups. In the transplant group the cell suspension, described in the section on cell preparation for transplantation, was injected though a 27-gauge needle into the myocardial infarct region (n = 5). One syringe containing 0.75 mL was injected into the center of the infarct region, and another syringe with the remaining 0.75 mL was injected into 4 regions in the periphery of the infarct region. Each injection site was closed with a purse-string suture. Culture medium (1.5 mL) was injected into the scar of the control hearts (n = 6) according to the same procedure used in the cell transplant group. The pericardium was closed with 4-0 Prolene sutures (Ethicon, Inc, Somerville, NJ). The ribs were approximated with No. 22 sternal wires, and the chest was closed in three layers. An intercostal block with 3 mL 0.25% bupivacaine (Marcaine E) was administered locally for extended postoperative analgesia. Analgesics and antibiotics were administered as mentioned previously.
Sestamibi (2-methoxy-2-methylpropyl isonitrile) technetium (Tc 99m) single-photon emission tomography
Global and regional perfusion and function of normal pigs were assessed by sestamibi technetium single-photon emission tomographic scans (MIBI) as previously described. 6 At 4 weeks after myocardial infarction but before transplantation a MIBI scan was performed on all the animals. The animals were then randomly separated into control and transplantation groups. Four weeks after cell transplantation the heart function of all the animals was evaluated again by MIBI scan. Each animal was sedated with ketamine at 20 mg/kg, electrocardiographic leads were applied, and 20 mCi of sestamibi technetium (E.I. du Pont de Nemours and Company, Wilmington, Del) was administered intravenously. Regional and global reconstructions of the heart were performed with AutoSpect software and quantified by Cedars-Sinai Quantitative Gated Spect software. Regional perfusion, wall motion and wall thickening, and global function were evaluated as described in a previous publication. 6
Cardiac function measurements
The heart function was evaluated with Millar micromanometer pressure and conductance volume catheters (Millar Instruments, Inc, Houston, Tex) 4 weeks after cell transplantation. 6 With the animal under general anesthesia, a midline sternotomy was performed to expose the heart. Calibrated pressure and volume catheters were inserted into the left ventricle through the apex. The pressure and volume data were collected with the Conduct-PC software (CardioDynamics, Zoetermeer, The Netherlands). Three baseline values were obtained. At least 3 values were recorded after clamping of the superior and inferior venae cavae until the left ventricle had emptied, as indicated on the volume tracing. Parallel conductance was evaluated after the injection of hypertonic saline solution into the pulmonary artery, and the volume measurements were corrected for the parallel conductance. The volume measurements were normalized for body weight. Pressure-volume loops before and after vena cava occlusion were plotted. The area within each curve was plotted against the end-diastolic volume to evaluate the preload recruitable stroke work as previously described elsewhere. 6
Heart morphologic measurements
Ventricular volume
After the function measurements the heart was relaxed by perfusing it with 20-mmol/L potassium chloride in saline solution and then excised. The left ventricular chamber volume was measured by the technique of Pfeffer and Braunwald. 7 A balloon was inserted into left ventricle. The balloon was increased in size by the addition of saline solution until the ventricular pressure reached 30 mm Hg. The injected saline solution volume was recorded as passive ventricular volume.
Planimetry
The size of the infarct region of the heart was measured. 8 After the passive volume measurement was completed, the heart was fixed in distention (30 mm Hg) with an intraventricular balloon with 10% phosphate-buffered formalin solution for 2 weeks. The heart was cut into 5-mm thick sections. Heart sections were photographed and the scar area was quantified with computerized planimetry (Jandal Scientific Sigma-Scan, Corte Madera, Calif).
Histologic studies
Tissue samples (0.5 cm3) from the transplant and control sites were collected from the fixed heart after the heart morphologic study. The tissues were embedded in paraffin and cut into 10-µm thick sections. The sections were serially rehydrated with 100%, 95%, and 70% ethanol after deparaffinization with toluene. The sections were stained with hematoxylin and eosin for cell and blood vessel identification. The sections were also immunohistochemically stained for BrdU and troponin I.
Angiogenesis
Blood vessels in hematoxylin and eosin-stained tissue samples obtained from three locations within the infarct region of each pig were identified. The vascular density in each tissue section was counted at 400 magnification by an observer blinded to the treatment group. Five high-power fields in each section were randomly selected and their vascular densities, expressed as blood vessels/0.2 mm2, were averaged. Averages of 5 fields and 3 samples from each animal were used for comparison.
Immunohistochemical staining
Endogenous peroxidase in the sample was blocked with 3% hydrogen peroxide for 10 minutes at room temperature. The sample was treated with pepsin for 5 minutes at 42°C and with 2N hydrochloric acid for 30 minutes at room temperature. After being rinsed with PBS three times, the samples were incubated with monoclonal antibodies against BrdU or PBS (negative control) in a moist chamber for 16 hours at room temperature. The slides were rinsed with PBS, incubated with secondary antibody, immersed in diaminobenzidine and hydrogen peroxide solution, and photographed as described in the section on immunohistochemical staining.
Data analysis
All data were expressed as mean ± SE. The perfusion and wall motion measurements and the left ventricular volumes and ejection fractions obtained from the MIBI scans were subjected to 2-way analysis of variance. Left ventricular pressure and volume data were subjected to an analysis of covariance, evaluating group, time, and interactive group and time effects across the range of ventricular volumes. Other variables were assessed by 2-way analysis of variance or, when appropriate, by the t test.
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Results |
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-smooth muscle actin. Desmin was observed in 30% ± 8% of the cultured cells (Figure 1). None of the cells stained positively for bone, cartilage, CD34, or troponin I. The in vitro BrdU labeling efficiency of the stromal cells was 80% ± 10%.
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, a). No BrdU-labeled cells were found in the host myocardium or in the control hearts. Some of the BrdU-labeled cells in the transplant area contained organized sarcomeres and Z-bands and stained positively for cardiac-specific troponin I, whereas other BrdU-stained cells appeared to become interstitial cells (fibroblasts; Figure 2, b). Gap junctions were present between the BrdU-labeled cells. No junctions were seen between the BrdU-labeled cells and the host cardiomyocytes. The capillary density in the transplanted infarct region (9.2 ± 1.1 blood vessels/0.2 mm2) was greater (P < .05) than that in the control infarct region (3.4 ± 0.4 blood vessels/0.2 mm2). Some endothelial cells in the blood vessels in the transplant sites stained positively for BrdU (Figure 3).
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, b). Cell transplantation increased wall thickening significantly (P < .05) relative to the control group (Figure 4, c). The hearts with transplanted cells had better global function than did the control hearts (Figure 5). Stroke volumes were increased (P < .05) in the transplant group but not in the control group (Figure 6, a). The increased stroke volumes were achieved at lower end-diastolic volumes (P < .05 by analysis of covariance). Ejection fraction was increased in the transplant group and decreased in the control group, but the difference was not statistically different (Figure 6, b).
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Discussion |
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6 skeletal myoblasts, 9 smooth muscle cells, 10 and bone marrow cells 5 have been demonstrated to prevent heart failure after a myocardial injury. The advantages of bone marrow stromal cells include the clinical ease of obtaining a bone marrow aspirate and the possibility of differentiating the stromal cells into cardiomyocytes that may form gap junctions and beat synchronously with the host myocardium (myogenesis). 1 In addition, the stromal cells may differentiate into endothelial progenitor cells that may participate in neovascularization after transplantation (angiogenesis). 2
Shake and colleagues 4 purified myogenic cells from the bone marrow and transplanted these myogenic cells into the infarcted myocardium of porcine hearts. The cells survived in the transplanted area, formed a muscle tissue, reduced wall thinning by 26%, and attenuated regional contractile dysfunction relative to the control media-injected hearts. Orlic and associates 11 transplanted cultured bone marrow stem cells into viable ventricular myocardium adjacent to a recent infarct in a murine myocardial infarct model. The transplanted cells formed myocardium that occupied part of the infarct zone. The newly formed myocardium consisted of proliferating cardiomyocytes, endothelial cells, and smooth muscle cells derived from stem cells. Myocardial function of the hearts with cell transplants was significantly better than that of the control hearts. We previously used 5-azacytidine to induce cultured rat bone marrow stromal cells to become myogenic cells in vitro. 5 The cultured 5-azacytidine-treated stromal cells formed more myotubes at confluence than did the untreated stromal cells at confluence. Both the chemically induced and the untreated bone marrow stromal cells were implanted into transmural myocardial scars produced by cryoinjury in a rat model. Only the hearts with the 5-azacytidine-treated stromal cell transplants had improved cardiac function relative to control hearts that received culture medium alone. Neither fresh bone marrow nor cultured but untreated cells improved function. We attributed the effectiveness of 5-azacytidine treatment in improving myocardial function to an increased conversion in culture of stromal cells to myogenic progenitor cells, 12 because only muscle cell transplantation has been demonstrated to preserve ventricular function. 6,9,10,13
Conversion of bone marrow stromal cells to a myogenic phenotype was important in inducing myogenesis in myocardial scar tissue. 5-Azacytidine methylated DNA is thought to alter gene expression. 14 The combination of 5-azacytidine and the myogenic determination gene myoD was found to be more effective in increasing the frequency of myogenic conversion than was chemical induction alone. 15 The host cardiac milieu may also contribute to the conversion of stromal cells to cardiomyocytes after cell transplantation. 3 Alternate approaches include electrical stimulation, pressure, and stretch which also may induce myogenic differentiation of stromal cells and promote cell-to-cell integration and modification of the extracellular matrix. 16
Immediately before transplantation most of the 5-azacytidine-treated stromal cells had assumed a myogenic phenotype, with 80% staining positively for -smooth muscle actin and 30% staining positively for desmin. 17,18 Four weeks after implantation the transplanted cells had formed islands of cardiac tissue in the myocardial infarct region, and many of the cells stained positively for BrdU (labeled before transplantation, Figure 2
). The BrdU-stained cardiomyocytes contained organized sarcomeres and Z-bands and stained positively for cardiac-specific troponin I. Most of the well-defined islands of BrdU-stained cardiac tissue were located in the periphery of the infarct region, near the preserved host myocardium. Many of the transplanted porcine stromal cells formed junctions between the cells that were more distinct than those we found when rat stromal cells were implanted into the center of a homogeneous scar. 5 The better-differentiated cell-to-cell connections could represent a species difference but more likely reflect the transplantation of porcine stromal cells closer to functioning myocardium. The implanted rat cells in the scar may have been too distant from the viable recipient cardiomyocytes to be influenced by the milieu of the host myocardium. Similar to the findings of Orlic and associates 11 with a murine model, we showed that transplanted porcine stromal cells formed cardiomyocytes and endothelial cells in the infarct region.
Within the islands of BrdU-labeled cardiac tissue were capillaries lined with some BrdU-labeled endothelial cells (Figure 3). Kobayashi and coworkers 19 also found that bone marrow cell implantation induced angiogenesis in a rat left anterior descending coronary artery ligation model. Asahara and colleagues 2 demonstrated that circulating bone marrow endothelial progenitor cells entered the infarct region after left anterior descending coronary artery ligation in the mouse and were associated with sprouting blood vessels in the border of the infarct, perhaps contributing to the neovascularization of the infarct region. The treatment of an infarcted region with vascular endothelial growth factor mobilized endothelial progenitor cells from the bone marrow for blood vessel formation. This can be accomplished more efficiently by direct transplantation of bone marrow cells into the infarct region. In our study the transplanted stromal cells contributed about 10% of the endothelial cells of newly formed blood vessels according to the percentage of BrdU-labeled cells lining the capillaries. Because stromal cells are known to secrete vascular endothelial growth factor, 20 the transplanted stromal cells also accelerated neovascularization other than by direct involvement in blood vessel formation.
The improvement in cardiac function of the heats with stromal cell transplants relative to the control hearts resulted from the preservation of left ventricular volume. In the control hearts the infarct region thinned and dilated as a result of remodeling of the infarct scar, with a resultant deterioration in ventricular function. This phenomenon can be explained by the Laplace Law (
= Pr/w, where is wall stress, P is transmural pressure, r is the radius of the ventricular chamber, and w is wall thickness). The transplanted cells maintained the thickness and probably the elasticity of the scar, stabilizing the infarct region, preventing left ventricular chamber dilatation, and thus avoiding the increased left ventricular wall stress seen in the control hearts. Transplants of heart cells, 6 skeletal muscle cells, 9 and smooth muscle cells 10 have prevented scar thinning and chamber dilatation and improved heart function. This has not proved the case with a nonmuscle cells, such as endothelial cells. 13
The cell transplantation also improved regional function. Both regional thickening and wall motion were better in the transplant group than in the control group. Similar results have been reported in experimental 21 and clinical 22 skeletal myoblast transplantation. The mechanism responsible for the improved regional contractility has not been determined. The transplanted stromal cell-derived cardiomyocytes may have been beating, and those implanted near to the host myocardium may have been beating synchronously with the heart. However, neither heart cells nor bone marrow stromal cells have been shown to beat synchronously with the host heart, although both communicate with each other by gap junctions. Neither skeletal muscle myoblasts nor smooth muscle cells beat synchronously, and yet both have contributed to improved regional and global function. A more likely explanation is that the improvement in regional function resulted from angiogenesis induced by the stromal cell engraftment. Increased perfusion could have started hibernating host cardiomyocytes, particularly those in the border zone, beating synchronously with the heart. Regional contraction may have been improved by the tethering effect of the adjacent myocardium. 23 Increasing the elasticity of the infarct region would contribute to improved regional function from adjacent regions. The improvement in regional function probably resulted from a combination of factors, including myogenesis and angiogenesis.
This study has important limitations. The small number of animals limited the detection of smaller differences between groups. The pigs in this study were young and growing, and their bone marrow may have contained more cardiomyocyte progenitor cells than would be found in older animals. Primary cell cultures from young animals grow more rapidly than do cells obtained from older animals. For stromal cells transplants to be successful in adults, sufficient numbers of cardiomyocyte progenitor cells must be obtained, and their rate of cell division must be rapid enough to provide the number of cells required to repopulate an infarct. Although we found stromal cell-derived cardiomyocytes in the transplant region that were connected with each other, we did not demonstrate that these cells communicated with the host myocardium. We could not determine whether the transplanted cells were beating. Future studies are needed to determine the dose-dependent effects of implanted stromal cells on heart function and arrhythmias for at least 1 year.
In summary, chemically induced porcine bone marrow stromal cells obtained from young animals was successfully transplanted into myocardial scar tissue caused by a coronary artery occlusion. The transplanted cells formed capillaries and islands of cardiac tissue that contained differentiated cardiomyocytes, and the transplantation improved ventricular function relative to that of control hearts.
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