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Ann Thorac Surg 2001;71:1724-1733
© 2001 The Society of Thoracic Surgeons
a Department of Cardiac Surgery, The National University Hospital of Singapore, Singapore
b Department of Obstetrics & Gynecology, The National University Hospital of Singapore, Singapore
c Division of Cardiothoracic Surgery, Imperial College School of Medicine at The National Heart and Lung Institute, London, England, United Kingdom
Address reprint requests to Dr El Oakley, Department of Cardiac Surgery, National University Hospital of Singapore, 5 Lower Kent Ridge Rd, Singapore 119074
e-mail: eloakley{at}hotmail.com
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Abstract |
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 Top Abstract IntroductionPotential sources of muscle...Effects of cell transplantation...References |
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Introduction |
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TopAbstractIntroductionPotential sources of muscle...Effects of cell transplantation...References |
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Advances in molecular biology and gene transfer techniques have paved the way for the development of a new field in biomedical engineering, tissue engineering. Molecular manipulation and transplantation of muscle cells are exciting possibilities for assisting the failing myocardium [8, 9]. Cellular transplantation also has the potential to be a vehicle for gene therapy to induce immune tolerance, to stimulate angiogenesis, and to treat primary cardiomyopathies.
Direct induction of cardiomyocyte proliferation in the diseased myocardium is probably the ultimate aim for cell-mediated myocardial repair. However, adult mammalian cardiomyocytes lack the potential to proliferate [1, 2], and thus this approach remains elusive. Consequently, many investigators seek alternative sources for myocytes. We anticipate that within the next decade patients’ own cells will be used as a reliable source of myocytes for organ repair or replacement. The use of embryonic, fetal, and neonatal myocyte allografts are and could remain hampered by the ethical dilemma of using fetal and neonatal tissues for medical purposes. Furthermore, the potential need for a large number of cells to repair an average-size scar in an adult human heart renders this approach rather cumbersome.
To understand the molecular and biologic basis for augmenting heart function, the reader is referred to previously published reports [10, 11]. In this review we will discuss the published results of myocyte transplantation, with emphasis on potential sources of cells, genetic transformation of skeletal myoblasts for myocardial repair, and the effects of experimental cell transplantation on cardiac function.
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Potential sources of muscle cells |
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TopAbstractIntroductionPotential sources of muscle...Effects of cell transplantation...References |
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Human embryonic stem cells (ES cells) are derived from the inner cell mass (ICM) and do not form a discrete part of an individual embryo, because one or more of these ICMs can be removed from the blastocyst (for preimplantation diagnosis) without affecting subsequent fetal development. These cells are not equivalent to embryonic cells. For those reasons many scientists, abiding by recommendations of the National Institutes of Health’s Human Embryo Research Panel, have continued their research on these cells. Human embryonic stemlike cells were first isolated and cultured from the ICMs of human preimplantation embryos (blastocysts) by Bongso and associates [13, 14]. Nine subjects in an in vitro fertilization program donated 21 spare embryos for this study. All 21 embryos were grown to the blastocyst stage (day 5) on human fallopian tube epithelial feeder layers and then encouraged to hatch and allow the ICMs to attach to the feeder layers in the presence of 1000 U/mL of human leukemia inhibitory factor (LIF) to prevent differentiation. Nineteen of the 21 embryos produced healthy ICMs (ES cell-like growth) that could be subcultured over two generations without differentiation. The cells were confirmed as ES cells by their morphologic characteristics (high nuclear:cytoplasmic ratios and prominent nucleoli), positive alkaline phosphatase staining, and normal karyotype. Although the production of the primordial germ layers in severely combined immunodeficient (SCID) mice was not done in that study, it was, however, the first report on the successful isolation of human ICM cells and their continued culture for at least two passages in vitro.
Thereafter, ES cell lines, derived from blastocysts, that could be grown through several generations were confirmed and reported for the rhesus monkey [15], and five clones of ES cells were reported for human cells [16]. Pluripotential stem cells also have been isolated and cultured from primordial germ cells of human abortuses. However, it is not known whether those cells termed "embryonal germ cells" have the same capacity to differentiate as that of blastocyst-derived human ES cells [17].
Recently, two ES cell-lines–HES-1 and HES-2–from human blastocysts were passaged up to the 45th and 25th generations, respectively. The pluripotency of these cells was shown by the formation of human germ-cell derivatives in SCID mice. These cells have been shown to differentiate in vitro into nerve cells without using any specific agent or transgene [18].
It is also theoretically possible to prepare a patient’s own ES cells, which can be used for direct autotransplantation. For example, a differentiated somatic cell of a patient can be introduced into an enucleated human or animal oocyte, a process known as nuclear transfer [19]. The fused product is then exposed to an electrical pulse that stimulates the production of ES cells. These cells, which carry the patient’s own genome, can then be used for organ repair. The production of pluripotential ES cells from a human source will have tremendous potential in treating a variety of incurable diseases. In addition to being used to treat heart failure and Parkinson and Alzheimer diseases, these cells will be a powerful tool in developing drugs for gene therapy, and for the study of early human embryogenesis.
Allogeneic cardiac myocytes
The concept of using fetal and neonatal cardiac myocytes was enhanced by the results of earlier experiments [20–23]. When sections of ventricular myocardium were grafted into the anterior chamber of the eye, kidney, skeletal muscle, and scar tissues, researchers found that ectopic myocardium could survive for at least 6 months [24–26]. The grafts established vascular networks with the host circulation and maintained native structural and functional characteristics.
Many independent groups successfully transplanted fetal and neonatal cardiac myocyte suspensions directly into the myocardium [27–29]. Those studies used allogeneic or xenogeneic donors, including one study in which human fetal cardiomyocytes were grafted into rats [28]. Grafted fetal and neonatal rat cardiomyocytes were reported to have the ability to form mature grafts in syngeneic heart, acutely injured myocardium, and granulation tissue in the heart [30]. Currently fetal cardiac myocytes have proved to be the most rewarding source for cell transplantation because of their ability to integrate into the recipient myocardium both structurally and functionally. The first published study of improved hemodynamics after cell transplantation into diseased myocardium used fetal cardiac myocytes [29].
Transgenic neonatal and fetal cardiac myocytes
The effects of targeted oncogene expression on adult cardiomyocytes are poorly understood. Until and unless factors that induce controlled proliferation of adult cardiomyocytes are identified, transgeneic animal models will remain the main source of cardiomyocytes for experimental studies. Transgeneic animals are an invaluable source of cells in many fields of biomedical research, including tissue engineering of cardiac myocytes [9].
Transgenic mice expressing the fusion gene atrial natriuretic factor SV40 T-antigen (ANF-TAG) developed right atrial tumors containing spontaneously contracting, differentiated myofibers that contained sarcomeric myosin and immunoreactive ANF secretory granules [31]. Although the primary ANF-TAG cardiomyocyte tumors did not enable researchers to establish a cell line in vitro, one tumor (AT-1) had marked growth enhancement when implanted in syngeneic hosts [32]. AT-1 cells subsequently were shown to divide in culture with a limited number of passages [32]. Transgenic mice carrying a fusion gene composed of the cardiac 
-myosin heavy chain (MHC) promoter and the SV40 early antigen expressed TAG in atrial and ventricular myocytes [33]. Myocytes isolated from those transgenic tumors proliferated in culture and retained a differentiated phenotype, as evidenced by spontaneous contractile activities.
The ability of AT-1 cells to form stable intramyocardial grafts was tested by implanting these cells into the ventricular wall of syngeneic mice [34]. The animals were allowed to survive for up to 4 months postoperatively. In half the mice a viable intracardiac graft developed. No evidence of chronic graft rejection was detected on the basis of detailed immunohistochemical staining of the graft sites. The engrafted cells were identified by incubating samples of the recipients’ myocardia with polyclonal rabbit anti-TAG antibodies and were visualized by diaminobenzidine reaction with nickel enhancement. Black precipitates were observed over cardiomyocyte nuclei in the graft but not in the host myocardium, confirming that these cells were viable AT-1 grafts. Tritiated thymidine incorporation analysis showed that only 10% of the viable AT-1 cells could synthesize DNA, which is considerably less than the proportion of AT-1 cells cultured in vitro with that capability [35]. In this study, electron microscopic analysis showed that, despite the presence of abundant gap junctions within the grafted tissue, there were no junctions between AT-1 cells and host ventricular cardiomyocytes.
Further studies using myocytes from AT-1 transgenic fetal myocardium showed the presence of gap junctions between the graft and the myocardium of the syngeneic host [36]. AT-1 cells were also reported to have formed nascent junctional contacts with host porcine ventricular cardiomyocytes [37]. In the same study, fetal human cardiomyocytes grafted into porcine left ventricular wall were reported to be viable, lending weight to the feasibility of xenogeneic myoblast transplantation. These pioneering experiments have laid the foundation for cell transplantation for myocardial repair.
Developmental cardiomyocyte hyperplasia has been induced in embryos of transgenic mice by overexpressing the oncogenes c-myc and ras [38–40]. To avoid having to design a cell-specific promoter for every cell type in the transgenic animal, Noble and colleagues [41] developed transgenic mice in which a broadly potent immortalizing gene was expressed in all cell types of the body without perturbing the animal’s development. To date no cardiomyocyte cell line from those transgenic animals has been reported.
Autogenic sources
Skeletal muscle precursors
Unlike cardiac muscles, skeletal muscles retain an efficient capacity to regenerate because each muscle fiber bears a number of satellite cells under its basal lamina. These cells remain quiescent but are poised to proliferate in order to restore muscle cell loss after injury [42]. Cell lines derived from satellite cells of experimental animals comprise a pure population of myogenic cells that can be maintained in culture by repeated passaging over a long period [43]. Cell lines such as L6 (derived from rats) and C2C12 (derived from mice) maintain their ability to differentiate into myotubes in response to changes in tissue culture conditions [43, 44]. The potential for tumorogenesis and xenograft rejection of these cell lines prohibits their use in clinical practice. Therefore, the use of patients’ own skeletal satellite cells could be the most practical approach for cell transplantation for myocardial repair. Satellite cells can be propagated and genetically modified in vitro before implanting them into the diseased myocardium.
Conversely, genetic transformation of cardiac fibroblasts into cells expressing skeletal muscle contractile proteins might provide an alternative source of contractile tissue for the healing myocardium [45, 46]. This approach has been tested in many animal species where satellite cells derived from the animals’ own skeletal muscles were grafted into their infarcted myocardium. In one study, the grafted cells survived for 2 weeks [47] and in others for at least 3 months after the operation [48, 49]. Because skeletal muscles can acquire resistance to fatigue by changes made to their contractile proteins [50, 51], cellular grafts might offer long-lasting cardiac assistance.
Recent discoveries in muscle biology, however, suggest that there are two fundamental structural differences between skeletal and cardiac myocytes that could prevent skeletal muscle cell grafts from integrating into the recipient myocardium [52, 53]. The first of these structural variations is the lack of gap junction communication between skeletal muscle cells. Gap junctions (connexins) are direct communication channels between the cytoplasm of adjacent cardiac myocytes. These channels permit exchange of small metabolites and provide a low resistance electrical pathway between cardiac muscle fibers [53]. The other fundamental difference between the cell types is the dihydropyridine receptor (DHPR) phenotype [54, 55]. Dihydropyridine receptors determine the mechanism by which an electrical impulse travelling across the cell membrane is transformed into kinetic energy in the form of muscle contraction, a process otherwise known as excitation-contraction (EC) coupling [54–56]. Electrophysiologic studies have shown that there are two isoforms of the DHPR, one in the skeletal muscle and one in the cardiac muscle [56, 57]. In cardiac muscles, DHPRs function as fast calcium channels, which upon depolarization allow rapid influx of extracellular calcium ions into the cell. This calcium influx triggers the opening of the sarcoplasmic reticulum calcium-release channels. In skeletal muscles, however, DHPRs are believed to have a dual role, functioning both as slow calcium channels and as voltage sensors that directly control the release of calcium from the sarcoplasmic reticulum.
Injection of dysgenic myotubes, in which DHPRs are absent, with cDNA encoding skeletal DHPRs restores the slow calcium current and the skeletal type EC coupling [58]. Injection of cDNA encoding cardiac DHPRs (cDHPRs) into these myotubes produces rapidly activating calcium current and cardiac-type EC coupling [57, 59]. Electrophysiologic studies of dysgenic myotubes injected with cDHPRs also showed that the relationship between the amplitude of the calcium current and calcium transient and their dependence on test potential were similar to those of cardiac muscles [55, 57, 59]. These findings support the notion that genetic transformation of skeletal muscle cells into cells that express cDHPRs will have a significant effect on their EC coupling.
Genetic transformation of skeletal myoblasts, however, is dependent on an efficient gene transfer system that integrates the gene(s) of interest into the genome of the target cell. Retroviral vectors allow integration of the gene of interest into the genome of the target cell and its progeny. The retroviral vector MFG, based on the Moloney murine leukemia virus (a nonhuman pathogen), is the most widely used viral vector in experimental and clinical gene transfer studies [60]. We tested the ability of the MFG vector to transduce the skeletal myoblast cell line L6 [46]. The vector was engineered to carry the bacterial lacZ gene, encoding the enzyme ß-galactosidase. The L6 cells were plated and treated with supernatant from FLYA4 packaging cell line containing the MFGnlslac-Z vector for 3 days, after which they were fixed and stained for ß-galactosidase activity. We found that the MFG vector transduced 68.9% to 71.4% of the treated skeletal myoblasts. The level of transgene expression remained unaltered when the cells were allowed to divide 160 times over 4 months and to differentiate into myotubes. The connexin-43 gene was then cloned into the backbone of the MFG vector. This construct was used successfully to transduce the skeletal myoblast cell line L6 to express the gap junction protein connexin-43 (Yacoub and coworkers, unpublished data). Future studies will be aimed at coexpressing the cDHPRs in the same cell line. The contractile mechanism in these cells and its effects on myocardial performance await further evaluation.
Fibroblasts
A highly efficient method of converting human fibroblasts into myogenic cells by adenoviral-mediated MyoD gene transfer has been reported [61]. Fibroblasts were infected with a replication-defective adenoviral vector expressing full-length murine MyoD cDNA under the transcriptional control of Rous sarcoma viral long-terminal repeats. Conversion of murine fetal dermal fibroblasts to myocyte-like cells was achieved in 83% of the total cell population. The transformed cells were similar to the primary myogenic cells of the same species in terms of morphologic, immunohistochemical, and biochemical characteristics. The cells also formed apparently normal fibers when injected into a regenerating skeletal muscle of an immunodeficient mouse. The same technology has been applied to redirect cardiac fibroblasts into myogenic cells [62]. The same vector was used to induce MyoD expression in rat heart that had been injured 1 week previously. Double immunostaining showed that cells in the reparative tissue expressed embryonic skeletal MHC, suggesting that MyoD gene transfer can induce skeletal muscle differentiation in healing heart lesions.
Mesenchymal cells
Cardiomyogenic (CMG) cell line has been isolated from murine bone marrow stromal cells [63]. After a series of passages, attached marrow stromal cells became homogeneous. Those cells were then treated with 5-azacytidine to induce cell differentiation. Spontaneously beating cells were screened repeatedly by microscopic observation and constituted the CMG cells. These latter cells connected with adjoining cells through intercalated discs after 1 week, formed myotube-like structures, began beating spontaneously after 2 weeks, and beat synchronously after 3 weeks.
Various methods were used to identify the phenotype of the CMG cells. Expressions of atrial natriuretic peptide and brain natriuretic peptide were detected. The cells also stained positively with antimyosin, antidesmin, and antiactin antibodies. Electron microscopy showed an ultrastructure resembling cardiomyocytes, including typical sarcomeres, a centrally positioned nucleus, abundant glycogen granules, a number of mitochondria, and numerous atrial granules.
The CMG cells had several types of action potentials, including sinus node-like action potentials and ventricular cell-like action potentials, which became detectable 4 weeks after treatment. The proportion of cells producing the latter action potential gradually increased thereafter. All cells had a long action potential duration and plateau, a shallow resting membrane potential, and a pacemaker-like late diastolic slow depolarization.
Analysis of the isoform of contractile protein genes, eg, myosin heavy chain, myosin light chain, and -actin, indicated that the phenotype of the differentiated CMG cells was similar to that of fetal ventricular cardiomyocytes. They expressed Nkx2.5/Csx, GATA4, TEF-1, and MEF-2C genes before the final 5-azacytidine treatment and the MEF-2A and MEF-2D genes after the final 5-azacytidine treatment. This pattern of gene expression was similar to that of in vivo developing cardiomyocytes at the stage between the cardiomyocyte progenitor and differentiated cardiomyocyte.
Adult heart cells
Adult Sprague-Dawley rat heart cells harvested from the left atrial appendage increased in number ex vivo [64]. These cells were then injected into the center of the scar tissue, induced by cryoinjury, of the left ventricular free wall. Hemodynamic evaluation in a Langendorff preparation showed that the systolic and developed pressures were greater in the transplant group. Histologic studies confirmed survival of the transplanted heart cells, labeled with BrdU, within the scar tissue 5 weeks after transplantation. However, the graft did not have the typical structure of cardiac muscle, ie, the cells were not arranged in a consistent orientation as found in vivo in the atrium or the ventricle. The autologous cell transplantation did not induce inflammatory responses associated with immunologic rejection. Also, the scar was smaller and thicker in the transplant group. The left ventricular volume was smaller as well. The authors concluded that the transplantation of cultured autologous adult atrial heart cells limited scar thinning and dilatation, and improved myocardial function compared with the control group.
Manipulating the mitotic clock of cardiac myocytes
The common belief that cardiac myocytes have entered the nondividing state of replicative senescence has been challenged by the results of recent experimental studies [65]. Replicative senescence seemed to be dependent on the overall number of cell divisions and not on metabolic or chronologic life span; ie, the potential for cell proliferation is dependent on a mitotic clock. The telomerase enzyme activity is thought to control the length of telomere and the mitotic clock. Induced gene expression of the telomerase enzyme in human epithelial cells and fibroblasts was associated with longer telomere and an increase in the total number of cell divisions compared with telomerase-negative control cells. Further studies are needed to determine whether these findings can be translated into inducing cardiac muscle cell proliferation in vivo.
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Effects of cell transplantation on myocardial function |
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TopAbstractIntroductionPotential sources of muscle...Effects of cell transplantation...References |
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Li and colleagues [66] injected rodent fetal cardiac myocytes labeled with the ß-galactosidase gene into the myocardium of allogeneic adults. The recipient myocardium had been injured with a cryogenic probe 4 weeks earlier. After 4 weeks of cell transplantation the heart was explanted and perfused in a Langendorff apparatus. The left ventricular systolic pressure and the developed pressure (the difference between systolic and diastolic pressures) were measured using a balloon catheter implanted into the left ventricle. Compared with control animals, the transplanted group had significantly greater systolic and developed pressures. The average scar size in the transplantation group was less than that in the control group. The hemodynamic benefits in the transplantation group were attributed to significant limitation of the size of myocardial scarring.
Scorsin and coworkers [27] transplanted allogeneic cardiomyocytes from fetal rats into the hearts of adult female animals. The recipient hearts were made ischemic by occluding the proximal left anterior descending coronary artery for 45 minutes before cell transplantation. Cyclosporine was given to suppress the immune system. One month after implantation, M-mode and 2-dimensional echocardiographic studies were done. The animals that received cell transplant had better postinfarct function than controls, as shown by significantly higher ejection fractions and cardiac outputs. There was no histologic evidence of rejection. Infarcted areas in the transplantation group were smaller than those in the control group. Because all recipients were female, the Y chromosome was used as a marker for transplanted cells.
Taylor and associates [67] transplanted autologous skeletal myoblasts into rabbit myocardia. The animals’ hearts underwent cryogenic injury to produce transmural lesions in the myocardium. Unlabeled autologous skeletal myoblasts were transplanted into the damaged hearts 1 week later. Three to six weeks after implantation, elongated structures resembling striated skeletal myotubes were observed as isolated tissue islands surrounded by infarcted tissues. These structures stained positively for myogenin, a factor specific to the transplanted myocytes. Seven of the 12 rabbits transplanted with skeletal myoblasts had successful engraftment. This was associated with improved regional systolic and diastolic functions, as demonstrated by in vivo assessment with ultrasonic dimension transducers. In five of the seven rabbits, improvement in contractility reached statistical significance compared with the control group. However, the other animals that had transplants did not demonstrate improved function. Histologic examination of these myocardial samples also showed few myogenin-positive myocytes in the damaged regions. The reason for this discrepancy was unclear. Light microscopy of the myogenin-positive sections in the functionally improved group showed hallmarks of skeletal myotubes eg, ribbon-like myofibrils, and peripheral localization of nuclei. Few blood vessels were seen near the engrafted sites. However electron microscopic analysis of the same regions showed single cells joined by intercalated discs, a distinctly cardiac feature–rather than multinucleated skeletal myotubes. The authors further hypothesized that skeletal myoblasts, in the myocardial milieu, will transform into cardiac myocytes.
Although the findings of Taylor and associates [67] contradict the concept of terminal differentiation of skeletal muscle cell line [48], they are supported by work from the same group [47]. The latter transplanted autologous immature skeletal myoblasts of rabbits into a cryogenically injured area of the left ventricle. Immunohistochemical staining showed two populations of muscle cells within the damaged myocardium. At the center of the graft, elongated structures staining positively for skeletal muscle-specific myogenin were seen; they were believed to have been derived from skeletal myoblasts. At the periphery of the lesion, myogenin-negative cells resembling immature cardiocytes, both in terms of striations and the central location of the nuclei, were also seen.
The hemodynamic benefits of skeletal muscle cell transplantation might not be due to direct skeletal myocyte contraction per se. Instead, improved ventricular function could result from amelioration of left ventricular remodeling after injury in the presence of grafted cells, as postulated by Sakai and coworkers [64]. In another study, that group transplanted three different fetal rat cell types (ventricular cardiomyocytes, gastric smooth muscles, and skin fibroblasts) into adult rats [68]. The purpose of using smooth muscle cells and skin fibroblasts was to assess the relative merits of myocyte contribution to cardiac function. Cell transplantation was done 4 weeks after cryogenic injury of the left ventricular wall. Four weeks later, cardiac function was assessed in a Langendorff preparation. Developed pressures, maximal rates of myocardial contraction, and relaxation were significantly greater in the transplantation group compared with the control group (without cell transplantation). These variables were maximal in the cardiomyocyte group but were not significantly different between the smooth muscle cell and fibroblast groups. End-diastolic pressures and left ventricular volume indices, however, were not significantly different among the three groups. Histologic studies showed the characteristic morphologic condition for each cell type. The transplanted fetal cardiomyocytes also formed striated myocardium which, when excised, beat spontaneously and regularly. However, those cells were not labeled in order to differentiate them from the native cells that survived within the injured area.
In summary (Table 2), cell transplantation is an exciting approach for myocardial repair. Experimental evidence of direct hemodynamic benefits of cell transplantation is almost irrefutable. The ideal source of cells, however, is yet to be defined. The most practical and least ethically contentious source is the use of patients’ own cells. This avenue of research is still in its infancy and can be superceded by the use of exogenous cells, such as ES cells that can differentiate into cardiomyocytes.
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