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J Thorac Cardiovasc Surg 2003;125:361-369
© 2003 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology (CSP) |
From the Stem Cell Research Laboratory, The Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory, Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.
Received for publication Dec 21, 2001. Revisions requested March 18, 2002; revisions received May 23, 2002. Accepted for publication May 28, 2002. Address for reprints: Yong-Fu Xiao, MD, PhD, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 (E-mail: yxiao{at}caregroup.harvard.edu).
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Abstract |
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-myosin heavy chain and cardiac troponin I was greater in the infarcted area with embryonic stem cell transplantation than in the injured myocardium with medium injection. Single green fluorescent protein-positive cells with a rod shape and clear striations were observed in cardiomyocytes isolated from infarcted hearts with embryonic stem cell transplantation. In addition, the number of blood vessels in injured myocardium was greater in the cell-transplanted myocardial infarction group than in the medium-injected myocardial infarction group. |
Introduction |
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1 Only a small percentage of patients receive heart transplants because of this shortage of donors. New and effective therapies for patients with heart failure are therefore urgently required.
Recent studies have demonstrated that transplantation of cultured cells into damaged myocardium offers a new approach to restoration of the impaired cardiac function in either cryoinjured 2,3 or infarcted hearts. 4-9 Engrafted cells have been shown to survive, proliferate, and form gap junctions with the host myocardium. 7,10 In contrast, Watanabe and colleagues 11 found that fetal and neonatal pig cardiomyocytes and the cardiac-derived cell line HL-1 did not survive after grafting into infarcted pig myocardium. However, a recent study in mice showed that intramyocardial transplantation of bone marrow cells not only generated new myocardium but also significantly improved left ventricular (LV) function. 4 The underlying mechanism of these discrepancies may result from differences in the types of donor cells or the status of the host myocardium at the time of cell transplantation.
Embryonic stem cells, pluripotent cells containing the capacity for unlimited in vitro proliferation, may be useful to cardiogenesis. 12 Our recent study showed that embryonic stem cell transplantation was feasible in injured myocardium and improved cardiac function in rats with MI 6 weeks after transplantation. 13 However, the prolonged effects of embryonic stem cell transplantation on postinfarction failing hearts remain to be determined. It is therefore important to know whether the beneficial effects of cell transplantation could last for a longer period. This study investigated the effects of embryonic stem cell transplantation on mortality and cardiac function in rats 32 weeks after MI induction and cell implantation.
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14 Briefly, ES-D3 cells were cultured in Dulbecco modified Eagle medium on mitotically inactive mouse embryonic fibroblast feeder cells (American Type Culture Collection). The medium was supplemented with 15% fetal bovine serum, 0.1-mmol/L ß-mercaptoethanol (Sigma, St Louis, Mo), and 103 U/mL of leukemia inhibitory factor-conditioned medium (Life Technologies, Inc, Rockville, Md) to suppress differentiation. To initiate differentiation, embryonic stem cells were dispersed with trypsin and resuspended in the medium without supplemental leukemia inhibitory factor and cultured with the hanging drops method (approximately 400 cells per 20 µL) for 5 days. They were then seeded into 100-mm cell culture dishes. Beating cardiomyogenic clusters were dissected by use of a sterile micropipette and recultured for another 2 days at 37°C in a 98% humidified atmosphere with 5% carbon dioxide. Action potentials recorded in 2-week cultured beating embryonic stem cells (data not shown) were similar to those in cultured neonatal mouse cardiomyocytes. 13
Before transplantation, cells dissected from beating clusters were transfected with green fluorescent protein (GFP), a marker for identification of engrafted cells from host myocytes in injured myocardium. Plasmids with an immediate-early (IE) gene of human cytomegalovirus (CMV) promoter-enhancer driving GFP gene (5.7 kb) and Gene PORTER transfection reagent were obtained from Gene Therapy Systems Inc (San Diego, Calif). Embryonic stem cells (2 x 105 cells) were plated onto 100-mm dishes and were grown to 50% to 60% confluence on the day of transfection. The GFP transfection efficiency, as detected under fluorescent microscopy, was more than 90%. Two days after GFP transfection, cultured embryonic stem cells were digested with trypsin and resuspended in Joklik modified medium (Sigma) with a density of 107 cells/mL for cell transplantation. We observed under microscopy that about 40% to 50% of the cells used for transplantation were beating. In addition, after 11 days of culture by the hanging drops method without micropipette dissection of beating cells, flow cytometry revealed that 26% ± 1.2% (mean ± SEM, n = 5 runs) of embryonic stem cells were positive for cardiac -myosin heavy chain (-MHC).
Experimental myocardial infarction and embryonic stem cell transplantation
Experiments were performed in male Wistar rats (Charles River Laboratories, Inc, Wilmington, Mass) with an initial body weight of approximately 300 g. The investigation conformed to the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996 (NIH Publication No. 85-23). The protocol was approved by our institutional animal care committee. MI was created by ligation of the left coronary artery as previously described elsewhere. 15 Within 20 minutes after MI induction, 3 x 105 embryonic stem cells in 30 µL medium were injected with a tuberculin syringe into three different sites in infarcted hearts. Two injection sites were at the border of the ischemic area, and the other was in the middle of the injured area. The number of embryonic stem cells injected here was in the range (30,000 to 500,000 cells/animal) transplanted by other researchers in animals after MI. 4 Control rats with MI received the exact volume of the cell-free medium as received by the rats treated with embryonic stem cell transplantation. No experimental rats were treated with immunosuppressants during the 32-week follow-up, despite the xenogenic cell transplantation.
Survivals were evaluated in all groups during the 32-week follow-up. The study comprised of the following groups: rats with MI that received transplanted embryonic stem cells (MI plus embryonic stem cells, n = 26), control rats with MI injected with an exact volume of the cell-free medium (MI plus medium, n = 31), and a sham operation control group with neither ligation of the coronary artery nor intramyocardial injection (sham control, n = 23).
Echocardiographic study
Thirty-two weeks after transplantation, the animals (5 for each group) were anesthetized with pentobarbital. The echocardiographic procedure was performed as previously described elsewhere. 16 A commercially available echocardiographic system equipped with a 12.5-MHZ probe (Agilent Sonos 5500; Agilent Technologies, Palo Alto, Calif) was used in our experiments. Initially, a 2-dimensional short-axis view of the LV was obtained at the level of the papillary muscles. After optimizing gain settings and ensuring that the image was on axis, M-mode tracings were recorded through the anterior and posterior LV walls at a paper speed of 100 mm/s. This orientation was chosen to allow delineation of wall thickness and motion in infarcted and noninfarcted territories. The results were recorded on optical disks, and the M-mode tracings were analyzed. LV mass was calculated with a cube formula. Relative anterior wall thickness, relative posterior wall thickness, and LV internal dimensions were measured from at least three consecutive cardiac cycles. We also used endocardial fractional shortening and midwall fractional shortening as indices to estimate LV systolic function.
Measurement of hemodynamics
In another series of experiments, rats (n = 8 in sham control group, n = 8 in MI plus medium group, and n = 9 in MI plus embryonic stem cells group) were anesthetized again with pentobarbital at 32 weeks after MI induction and cell transplantation. Hemodynamic measurements were performed in vivo with a modification of a method described previously. 13,16 Briefly, a carotid artery of a rat (anesthetized by intraperitoneal administration of pentobarbital at 60 mg/kg) was isolated and cannulated with a 3F high-fidelity microtip catheter connected to a pressure transducer (Millar Instruments, Inc, Houston, Tex). The Millar catheter was carefully advanced into the LV. LV systolic and end-diastolic pressures, the maximum rate of LV systolic pressure rise (+dP/dtmax), and heart rate were monitored and recorded on a chart strip recorder. Rats were allowed to breathe spontaneously during hemodynamic measurements. After hemodynamic measurements, the rat was killed and the heart was rapidly excised. The LV, including the septum, was weighed and normalized for body weight. The ratio was calculated as index of hypertrophy.
Measurement of infarct size, identification of transplanted cells, and histologic analysis
Under pentobarbital anesthesia (100 mg/kg administered intraperitoneally), the rats (n = 11 in the sham control group, 12 in the MI plus medium group, and 10 in the MI plus embryonic stem cells group) were killed to evaluate morphologic characteristics and to identify the engrafted cells. The hearts were quickly removed and dissected into four transverse sections from apex to base. Subsequently, the transverse sections were embedded in tissue-freezing medium. Partial 5-µm transverse slices from each section were prepared for hematoxylin and eosin staining, and the images were digitized. Infarct size was calculated by dividing the sum of the planimetered endocardial and epicardial circumferences of the infarcted area by the sum of the total epicardial and endocardial circumferences of the LV. 17
The survival of engrafted cells was identified by GFP-positive tissue in frozen sections made from hearts with MI. Transformation of cardiaclike cells from engrafted embryonic stem cells was verified by antibody immunostaining for cardiac -MHC and cardiac troponin I (TnI). Briefly, frozen tissue sections were fixed in acetone at 4°C for 10 minutes and incubated separately with a goat polyclonal immunoglobulin G anti-TnI antibody (Santa Cruz Biotechnology, Inc, Santa Cruz, Calif) or a mouse anti--MHC monoclonal antibody (Berkeley Antibody Co, Richmond, Calif) for 60 minutes at room temperature. After washing with phosphate-buffered saline solution, sections were incubated with a rabbit antigoat conjugated rhodamine immunoglobulin G for TnI or a goat antimouse conjugated fluorescein immunoglobulin G for -MHC (Pierce Chemical Company, Rockford, Ill). Immunostaining was performed on serial sections of hearts with MI. To verify the survival and transdifferentiation of engrafted cells, single cardiomyocytes were enzymatically isolated from hearts (n = 4) at 32 weeks after MI induction and cell transplantation. The detailed isolation method is described in a previous report. 18
Measurement of capillary density
The effect of embryonic stem cell transplantation on angiogenesis was evaluated by counting the number of capillary vessels 3 within the infarcted zone from frozen sections with hematoxylin and eosin staining under light microscopy. A capillary vessel was defined as a vessel with a diameter less than 20 µm. The number of capillaries was counted under microscopy (x400 magnification) for five random fields in the infarcted area and presented as the mean of blood vessels per unit area (0.2 mm2).
Data analysis
All values are presented as mean ± SE. Data collected at the end of the 32-week follow-up period were evaluated by 1-way analysis of variance. If analysis of variance showed a significant difference, an unpaired Student t test was used to compare two individual groups. Survival during the 32-week observation period was analyzed by standard Kaplan-Meier analysis, and a statistical comparison between survival curves was made with the log-rank test.
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) demonstrated a significant increase (log-rank = 3.86, P < .05) in survival in the rats transplanted with embryonic stem cells compared with the animals injected with the cell-free medium.
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, B). These GFP-positive cells were rod shaped with clear striations, characteristic of adult mammalian cardiomyocytes (Figure 4, C). The average number of GFP-positive cells isolated from 4 rats after the 32-week follow-up was 1,929,500 ± 119,907 out of a total average of 16,263,900 ± 1,218,478 myocytes. The percentage of GFP-positive cells among total isolated LV myocytes was 11.9%, which is higher than the percentage of GFP-positive cells in rat hearts at 6 weeks after MI and embryonic stem cell transplantation (7.3%). 13 Hematoxylin and eosin staining of myocardial sections showed engrafted cells in injured myocardium at 32 weeks after embryonic stem cell transplantation (Figure 5, C). More -MHC (Figure 6, C) and cardiac TnI (Figure 6, F) were found in the cell-transplanted specimens, but only a limited number of sections were studied. These data suggest that engrafted embryonic stem cells not only survived in myocardium as long as 32 weeks after MI induction and cell transplantation but also differentiated into mature cardiomyocytes.
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Discussion |
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4-9 Electron microscopy has revealed that nascent intercalated disks may be formed in injured myocardium between engrafted cardiomyocytes and host cells. 10 Koh and coworkers 19 further confirmed gap junctions between engrafted cells and host myocytes. However, no data have shown the optimal cell type for cell therapy in the heart. Cardiomyogenic cells derived from embryonic stem cells may be a viable source for cell transplantation. Embryonic stem cells have been shown to differentiate spontaneously into the derivatives of all three primary germ layers 20 and to retain the ability to differentiate into most cell types of the body, including cardiomyocytes. 12 Furthermore, embryonic stem cells cultured within embryonic bodies can reproduce highly specialized phenotypes of cardiac tissue. 21 In our study, engrafted embryonic stem cells survived in injured myocardium.
Our previous 13 study showed that transplanted embryonic stem cells could differentiate into cardiomyocytes and subsequently enhance ventricular function at 6 weeks after MI induction and cell implantation. In this study engrafted embryonic stem cells improved cardiac function, which was evaluated by hemodynamic and echocardiographic measurements, for a much longer period. We did not perform simultaneous pressure and volume measurements, however, and we therefore did not evaluate load-independent indices of ventricular function. The survival of engrafted cells in injured myocardium was confirmed by the finding of strongly GFP-positive tissues in myocardium at 32 weeks after MI induction and cell transplantation. Single GFP-positive cells isolated from hearts with embryonic stem cell transplantation were rod shaped with clear striations. In addition, immunostaining for -MHC and cardiac TnI showed a higher proportion of injured myocardium with embryonic stem cell transplantation than with medium injection. Our data strongly suggest that the improvement in cardiac function may result from transformation of cardiomyocytes from implanted embryonic stem cells. Because we did not evaluate enough sections in individual animals to quantitate the extent of the engrafted embryonic stem cell transdifferentiation, however, more experiments are certainly required. In addition, histologic examination did not show significant evidence of immunorejection of engrafted cells. Neither infiltration of lymphocytes and macrophages (cell-mediated immunoreaction) nor antibody-mediated vascular damage was observed in hearts at 32 weeks after MI induction and cell transplantation. The underlying mechanism of the weak immunorejection has not been determined. A possible explanation is that the small quantity of transplanted embryonic stem cells may not be able to trigger an immunorejection, because embryonic stem cells express few membrane surface antigens. 22 From our previous experiments, 23 we learned that the surface membrane of human embryonic kidney cells does not express CD4 and CD8, which are crucial for immunoreaction. Additional experiments are surely required to understand the lack of immunorejection in animals transplanted with embryonic stem cells. Furthermore, we cannot be certain whether rejection reduced the beneficial effects of embryonic stem cell transplantation because of deficiencies in quantitative assessment of the extent of rejection.
Single cardiomyocytes showed that 11.9% of enzymatically isolated cells from LVs in the rats at 32 weeks after MI induction and cell transplantation were GFP positive. This percentage is greater than that in rats at 6 weeks after MI and cell transplantation (7.3%). 13 However, the functional improvements were similar in the rats at 6 and 32 weeks after MI and cell transplantation. This result suggests that the improvement of cardiac function reached a limited level after transplantation of a certain amount of embryonic stem cells. Damaged myocardial regions with enriched grafted cells were accompanied by new blood vessels found in our experiments, thus an angiogenetic effect may be crucial to the survival of transplanted cells. New blood supply to damaged myocardium may provide nutrition to implanted cells, allow an avenue for removal of cellular debris during primary injury, and also rescue some host myocytes injured in the ischemic area. These effects may help the heart to improve its function. The mechanism of the angiogenetic effect caused by embryonic stem cell transplantation remains to be determined. However, it is possible that transplanted embryonic stem cells may deliver strong signals, such as endothelial growth factors and insulinlike growth factors, to stimulate neovascularization in the surrounding tissues or that a portion of the implanted embryonic stem cells may transdifferentiate into the cell sources for revascularization. It has been reported that embryonic stem cells express vascular endothelial growth factors and cause an angiogenetic effect after cell implantation in infarcted myocardium. 24 In rat experiments of myocardial cryoinjury, Tomita and associates 3 counted capillary density and found that the number of capillaries was significantly greater in rats with transplantation of autologous bone marrow cells than in control animals. Neovascularization therefore may result in a reduction in infarct size of the heart, as shown by this study.
In summary, transplantation of embryonic stem cells caused a long-term improvement of heart function in rats after MI. This improvement may have resulted from transformation of cardiac myocytes and blood vessels by engrafted embryonic stem cells. This novel approach may offer insight into potential clinical therapy for MI and heart failure.
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Na+ channels. Am J Physiol Heart Circ Physiol. 2000;279:H35-46.This article has been cited by other articles:
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