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TISSUE ENGINEERING AND REGENERATIVE MEDICINE
Concise Review: Cell Therapy and Tissue Engineering for Cardiovascular Disease YUJI HARAGUCHI, TATSUYA SHIMIZU, MASAYUKI YAMATO, TERUO OKANO Key Words. Autologous stem cell transplantation • Cell transplantation • Stem/progenitor cell • Tissue regeneration • Transplantation
Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University, Tokyo, Japan Correspondence: Teruo Okano, Ph.D., Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 1628666, Japan. Telephone: ⫹81-35367-9945, ext. 6201; Fax: ⫹813-3359-6046; e-mail:
[email protected] Received September 20, 2011; accepted for publication November 16, 2011; first published online in SCTM EXPRESS January 26, 2012. ©AlphaMed Press 1066-5099/2012/$30.00/0 http://dx.doi.org/ 10.5966/sctm.2012-0030
ABSTRACT Cardiovascular disease is a major cause of morbidity and mortality, especially in developed countries. Various therapies for cardiovascular disease are investigated actively and are performed clinically. Recently, cell-based regenerative medicine using several cell sources has appeared as an alternative therapy for curing cardiovascular diseases. Scaffold-based or cell sheet-based tissue engineering is focused as a new generational cell-based regenerative therapy, and the clinical trials have also been started. Cell-based regenerative therapies have an enormous potential for treating cardiovascular disease. This review summarizes the recent research of cell sources and cell-basedregenerative therapies for cardiovascular diseases. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:136 –141
INTRODUCTION Various clinical therapies for cardiovascular diseases are performed and treat many patients who suffer from these diseases. However, at present, cardiovascular diseases still remain a major cause of death, especially in the Western world [1]. Various recent reports have demonstrated that cell-based regenerative medicine has a promising potential for recovering severe cardiovascular disease. Cell therapy by the direct injection of dissociated cells has been clinically performed (Fig. 1) [2–5]. More recently, tissue engineering has emerged and focused as the second-generation of cell-based regenerative therapy [6 –9]. Tissue engineering currently stands on a concept that biodegradable three-dimensional (3D) scaffolds are used as an alternative for extracellular matrix (ECM), and cells are seeded into the scaffolds (Fig. 1) [10]. In contrast to the scaffold-based technology, “cell sheet engineering” allows us to fabricate 3D tissues by layering cell sheets without scaffolds [11, 12]. Heart tissue consists of many beating cardiomyocytes, and the rhythmical beating of cardiomyocytes contributes the rhythmical contractions of heart tissue. The stenosis of coronary artery, which supplies oxygen and nutrients to heart tissue, may induce the death of cardiomyocytes and sequential acute myocardial infarction [13, 14]. In fact, acute myocardial infarction may induce the cell death of approximately one billion cardiomyocytes [15]. The death of a large number of cells may induce sequentially the negative remodeling of left ventricular (LV), includ-
ing (a) tissue fibrosis, (b) the decrease of LV wall thickness, (c) LV dilatation, and (d) the decrease of LV contractile function, and eventually lethal cardiovascular disease. Although spontaneous tissue regeneration may occur during these events, the regeneration is clinically insufficient [16]. Thus, the supplying of beating and functional cardiomyocytes into damaged heart tissue is important in curing cardiovascular disease. However, at present, clinical trials using human cardiomyocytes have been unaccomplished. Several alternative autologous cell types, including skeletal myoblasts, bone marrow- and peripheral blood-derived cells, cardiac stem cells (CSCs), and endothelial progenitor cells (EPCs), have been reported as implantable cell sources. Generally, the transplantation of these alternative cells is thought to induce the regeneration of damaged heart tissue with neovascularization, the inhibition of negative LV remodeling, the recruitment of stem cells, and so on via possible paracrine effects by cytokine/chemokine productions from implanted cells. In this review, (a) the cell sources of cell therapy for cardiovascular disease, (b) cell injection therapy, and (c) scaffold-based and cell sheetbased tissue engineering are reviewed and discussed.
CELL SOURCES Embryonic Stem Cells and Induced Pluripotent Stem Cells Human embryonic stem cells (ESCs) [17] and induced pluripotent stem cells (iPSCs) [18, 19] can
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Figure 1. Cell-based regenerative therapy for cardiovascular disease. ESC/iPSC-derived cardiomyocytes, skeletal myoblasts, BM- and PBderived cells, CSCs, and EPCs are used as cell sources for the therapy of cardiovascular disease. The cell-based therapies are performed by using the injection of dissociated cells, scaffold-based tissue engineering, and cell sheet-based tissue engineering. Abbreviations: BM, bone marrow; CSC, cardiac stem cell; ESC, embryonic stem cell; iPSC, induced pluripotent stem cell; PB, peripheral blood.
differentiate into beating cardiomyocytes in vitro by several methods [18, 20 –23]. The character of ESCs/iPSCs is attractive as cell sources for cardiovascular disease, because other human stem/progenitor cells can hardly differentiate into beating cardiomyocytes. Various studies for enhancing cardiac differentiation from ESCs/iPSCs have been performed, and granulocyte colonystimulating factor, ascorbic acid, cyclosporine A, and p38 mitogen-activated protein kinase inhibitor have been reported to have a potential for inducing cardiac differentiation [24 –28]. The purification of cardiomyocytes from heterogeneous cell mixture, as well as cardiac differentiation, is important, because the contamination of immature stem cells induces to teratoma formation after the transplantation [23]. Thus, for enriching differentiated cardiomyocytes, many studies use various methods, for example, purification by using Percoll gradient centrifugation, drug selection by using gene-modified stem cells harboring drug resistance gene in the cardiac-specific gene locus, and the use of a fluorescent dye that labels mitochondria [29 –32]. After being transplanted, human ESC-derived cardiomyocytes survive for a long term, can integrate with the host cardiac tissue, and induce the improvement of cardiac function in damaged heart animal models [33–37]. In the case of ESCs/iPSCs, there are other problems, which still have to be solved on the realization of the clinical trial. On the other hand, the first clinical trial in spinal cord injury using cells derived from human ESCs has been performed, as Bretzner et al. described [38]. In the near future, human ES/iPS cell-derived cardiomyocytes could be used in clinical practice for cardiovascular disease.
Autologous Cells Autologous cells have already been used clinically. Skeletal myoblasts were used clinically as the first cell source for heart tissue repair [2]. Skeletal myoblasts can be isolated autologously and be easily and rapidly expanded in vitro. However, the injection
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therapy of dissociated skeletal myoblasts for human myocardial regeneration has been already abandoned in the United States at present. Bone marrow- and peripheral blood-derived cells are the most used cells in clinical trials for cardiovascular disease [5, 15]. Bone marrow- and peripheral blood-derived cells are a heterogeneous cell population containing monocytes, hematopoietic stem cells, and EPCs [5, 15]. Although EPCs are the progenitors of endothelial cells, human EPCs can also be differentiated into cardiomyocytes by coculturing with rat cardiomyocytes, although the efficiency was very low (0.4 ⫾ 0.03%) [39, 40]. On the other hand, another group was unable to confirm the differentiation of EPCs into cardiomyocytes [41]. Bone marrow cells also contain mesenchymal stem cells (MSCs), which have a multipotency including cardiac differentiation [15]. In addition to bone marrow-derived MSCs, some stem cells isolated from adipose tissues and menstrual blood have represented their regenerative potentials for heart tissue [42, 43]. Adipose tissue-derived stem cells have an angiogenic potential and can also differentiate into cardiomyocytes without the addition of 5-azacytidine [44, 45]. Interestingly, some clones of human menstrual blood-derived stem cells differentiated into spontaneously beating cardiomyocytes effectively by cocultivating with mouse cardiomyocytes [43]. CSCs, which express Islet-1, Sca-1, and c-kit, are also an attractive cell source [46, 47]. CSCs differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells [46]. Heart has a renewal ability at normal state, and the annual rate of turning over is 1% at the age of 25 and 0.45% at the age of 75 [48]. Because the expansion of CSCs after heart damage is insufficient, newly formed cardiomyocytes in vivo are unable to replace damaged heart tissue. Therefore, the isolation and in vitro expansion of CSCs are necessary. Lee et al. succeeded in isolating and expanding CSC from biopsied myocardium [49]. Clinical trials using autologous CSCs isolated from biopsy sample are now in progress.
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CLINICAL TRIALS OF AUTOLOGOUS CELL INJECTION THERAPY Cell injection therapies for cardiovascular disease have already been performed clinically. Although skeletal myoblast injections were performed via epicardium for patients who were treated with coronary artery bypass grafting and the phase I clinical trial showed the feasibility of the cell therapy, the risk of ventricular arrhythmias after the operation was increased [2]. The phase II trial showed that the injection of skeletal myoblasts failed to significantly improve heart function [3]. On the other hand, the clinical trial suggested the possibility that the injection of higher cell numbers may recover LV dilatation. Moreover, the other clinical trials of catheter-based skeletal myoblast injection via endocardium showed a functional efficacy [4]. However, at present, most scientific physicians believe that the injection of dissociated skeletal myoblasts is not suitable for further clinical application. Bone marrow- and peripheral blood-derived cells are also used clinically [5, 15]. Although three independent meta-analysis studies of injection therapies using these cells showed the overall feasibility and safety, the improvements of cardiac functions were modest (the increases of LV ejection fraction [EF] are 3.0%, 3.0%, or 3.7%; the reductions of LV end-systolic volumes are 4.7, 4.8, or 7.4 ml; and the reductions of myocardial lesion areas are 3.5%, 5.5%, or 5.6%, respectively) [15, 50 –52]. Although many cell injection therapies are now clinically performed and some therapies induce modest therapeutic effects, the efficacies are found to be unable to reach the level such that general clinicians think cell therapy is a reliable treatment. Cell injection therapy has significant difficulties regarding cell retention in the target tissue, and injected cells are largely washed out. Previous studies in rat models and clinical trials demonstrated that many injected cells died after the transplantation, and only a few transplanted cells were detected in the infarcted myocardium [53, 54]. Cells were largely found in the liver and spleen immediately after the transplantation [54].
TISSUE ENGINEERING Three-Dimensional Tissues Fabricated by Using Autologous Cells and Clinical Trials To overcome the problems accompanied with dissociated cell injection, tissue engineering is focused as a new generational cell therapy [9, 55, 56]. Tissue grafts fabricated by using autologous alternative cells have been used in various animal models, and the clinical trials have been performed already. The most popular approach of tissue engineering is based on a concept that 3D scaffolds are used as an alternative for ECM, and cells are seeded into the scaffolds (Fig. 1) [10]. Piao et al. used bone marrow cells as a cell source and biodegradable poly-glycolide-co-caprolactone (PGCL) as a scaffold [57]. The transplantation of bone marrow cell-seeded PGCL scaffold effectively attenuated LV remodeling and LV systolic dysfunction in a rat infarction model via the induction of neovascularization and the differentiation of stem cells into cardiomyocytes [57]. Tan et al. used small intestinal submucosa (SIS) as 3D scaffold [58]. Although the transplantations of both SIS and MSC-seeded SIS into the heart of an infarcted rabbit model induced significant improvement of the heart function, the MSC-seeded SIS was more effective [58]. The migration of MSCs from SIS into the infarcted area and the dif-
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ferentiation of MSCs into cardiomyocytes and smooth muscle cells were shown [58]. Chachques et al. have performed clinical trials by using autologous bone marrow cell-seeded 3D collagen type I matrix and showed the feasibility and safety of the tissue transplantation [59]. Cell sheet engineering using a unique temperature-responsive culture surface, which is covalently grafted with a temperature-responsive polymer, poly(N-isopropylacrylamide), has been originally developed in our laboratory (Fig. 1) [11, 12, 60, 61]. Three-dimensional tissue can be easily fabricated by layering cell sheets detached from temperature-responsive culture surfaces (Fig. 1) [11, 12]. In addition, cell sheets can be directly transplanted onto the heart surface without suture, and the cells within sheets can be effectively delivered without cell loss, because cell sheets preserve their own ECM [11, 12]. Memon et al. used autologous skeletal myoblasts and compared the therapeutic effects of the transplantation of skeletal myoblast sheets with those of myoblast injection in a rat infarction model [62]. The transplantation of skeletal myoblast sheets gave (a) significant improvement of damaged heart functions (improvement of LVEF and shortening of the percentage of fractional area) and (b) significant reduction of fibrosis in comparison to the injection of myoblasts, whereas the skeletal myoblast injection also gave improvement of the heart functions and reduction of fibrosis in comparison to the medium injection control [62]. Although the transplantation of cell sheets gave a significantly thicker anterior wall, there was no difference in the thickness between the cell injection and the control groups [62]. The enhanced productions of angiogenesis-related cytokines (vascular endothelial growth factor [VEGF] and hepatocyte growth factor [HGF]) and stromalderived factor-1 (SDF-1) from transplanted cell sheets could be one of the causes of the therapeutic effects [62]. VEGF is a strong angiogenesis factor, and HGF has an antiremodeling activity in infarcted heart as well as angiogenesis [63– 67]. SDF-1 recruits hematopietic stem cells and EPCs expressing CXCR4, which is the receptor of SDF-1 [62, 68, 69]. The skeletal myoblast sheet transplantation was confirmed to induce more significant and remarkable improvement in damaged heart functions than the injection of dissociated cells [62]. Sekiya et al. showed that the therapeutic effect reached a plateau at a quintuplet-layered cell sheet, because of the insufficient supply of oxygen and nutrition for skeletal myoblasts within thicker cell sheet constructs [70]. Kondoh et al. showed that the transplantation of skeletal myoblast sheets improved a cardiac performance and prolonged the life span of animals, associating with the reorganization of the cytoskeletal proteins of host cardiac tissue and the reduction of myocardial fibrosis, using a dilated cardiomyopathy hamster model [71]. The significant therapeutic effects by the transplantation of autologous skeletal myoblast sheets were also confirmed in large-animal modes (a pacing-induced canine dilated cardiomyopathy heart failure model and a porcine ischemic myocardium model) [72, 73]. The transplantations of several adult stem cell sheets (adipose-derived and menstrual blood-derived mesenchymal stem cell sheets, and CSC sheets) also gave favorable therapeutic effects in small-animal models [41, 74, 75]. Several trials to enhance the therapeutic effects were performed. Siltanen et al. used HGF overexpressed myoblast sheets in a rat infarction model [76]. Whereas the transplantation of HGF overexpressed skeletal myoblast sheets induced effectively a stimulated angiogenesis in the infarcted and non-infarcted areas, cardiac function was hardly enhanced by HGF [76]. Kobayashi et al. STEM CELLS TRANSLATIONAL MEDICINE
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showed that the transplantation of EPC cocultured fibroblast sheets improved heart function more significantly than only fibroblast sheet implantation or EPC injection [77]. On the basis of these favorable results in various animal models, a clinical trial using autologous skeletal myoblast sheets is now in progress.
Three-Dimensional Myocardial Tissues Fabricated by Using Cardiomyocytes Pulsatile 3D myocardial tissues, like heart tissues, can be fabricated by tissue engineering. Li et al. fabricated 3D myocardial tissues, which beat spontaneously in vitro, by seeding fetal rat cardiomyocytes into a gelatin mesh [6]. The 3D tissue grafts contracted constantly and spontaneously even after transplantation onto the subcutaneous tissue of rats [6]. After being implanted onto myocardial scar part, the cardiomyocytes within the graft survived and formed junctions with the host heart [6]. Leor et al. fabricated 3D myocardial tissue by using neonatal rat cardiomyocytes and 3D porous alginate scaffolds, and transplanted the fabricated myocardial graft into rat infarcted models [7]. At 9 weeks after the implantation, well-formed myofibers with typical striation, gap junctions, and a large number of blood vessels were observed within the implanted graft [7]. The 3D scaffold was almost completely degraded after 9 weeks [7]. The transplantation of the 3D tissues induced significant improvement of damaged heart functions, namely, the attenuation of LV dilatation and the recovery of LV contractility as compared with the sham control groups [7]. Zimmermann et al. fabricated a 3D myocardial tissue by mixing neonatal rat cardiomyocytes, collagen type I, and a basement membrane protein mixture [78]. The myocardial tissue beat spontaneously, synchronously, and macroscopically as heart tissue [78]. More large-size engineered myocardial tissues (thickness/diameter ⫽ 1– 4 mm/15 mm) were fabricated and transplanted on rat infarcted models [79]. After being transplanted, engineered myocardial tissue showed an electrical coupling with the host myocardium without arrhythmia [79]. Furthermore, the transplantation of the engineered tissue graft gave improvements of damaged heart function after infarction, namely, (a) induction of systolic wall thickening of the LV and (b) improvement of fractional area shortening [79]. Zhao et al. fabricated 3D myocardial tissues by mixing rat cardiomyocytes, collagen type I, and matrix factors and showed that optimum cell densities and collagen quantities for fabricating pulsatile 3D tissues with characteristic features similar to native myocardium [80]. Engelmayr et al. used an accordion-like honeycomb microstructure as a scaffold to promote the formation of 3D myocardial tissue grafts having aligned cardiomyocytes and mechanical properties that more closely resembled the native heart [81]. Ott et al. fabricated 3D myocardial tissue by reseeding neonatal rat cardiomyocytes into decellularized rat whole hearts prepared by coronary perfusion with detergents [82]. During this, heart tissues were maintained up to 28 days by coronary perfusion in a bioreactor that simulated myocardial physiology; the macroscopic contractions of the tissues were observed at day 4, and under physiological load and electrical stimulation, at day 8 the tissues generated pump function, which was equivalent to ⬃2% of adult or 25% of 16-week fetal heart function [82]. Pulsatile 3D myocardial tissues also can be fabricated by layering cardiomyocyte sheets [83]. Two cardiomyocyte sheets can couple each other electrically and rapidly after layering via functional gap junction formation, and multilayered cardiomyocyte sheets beat spontaneously, synchronously, and macroscopically
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in vitro and in vivo [83– 85]. In addition, implanted cardiomyocyte sheets survived for a long term (⬎1 year) and showed the characteristic structures of native heart tissue (elongated cardiomyocytes, well-differentiated sarcomeres, gap junctions, and multiple blood vessels), as well as increased their size, conduction velocity, and contractile force in proportion to the host growth [83, 85, 86]. After being transplanted onto the heart of rat infarcted model, implanted layered cardiomyocyte sheets were coupled electrically to the host heart [87]. The transplantation of cardiomyocyte sheets improved the heart functions of a rat infarcted model, resulting in significant increases of LV wall thickness, decreases of cross-sectional LV area, and inhibitions of fibrosis and necrosis in the scar area [88]. The preservation of endothelial cells within cardiomyocyte sheets gave the formation of prevascular networks in vitro [89]. The transplantation of prevasculared cell sheets promoted a vascular connection with the host vessels and the therapeutic effects via the enhancing production of angiogenesis-related cytokines, namely, VEGF, HGF, and basic fibroblast growth factor [90]. Cell sheet-like constructs have been reported to be fabricated by using fibrincoated dishes, nanofibrous polycaprolactone meshes, or magnetite nanoparticles [91–94], and a concept of fabricating 3D tissues from two-dimensional confluent cells without scaffolds has spread worldwide. As described in the section on cell sources, clinical trials using human cardiomyocytes have been unaccomplished at present. On the other hand, recently, there have been several reports about fabricating 3D myocardial tissues using human cardiomyocytes differentiated from ESCs/iPSCs [95–99]. Tulloch et al. fabricated well organized heart-like human 3D myocardial tissues having blood vessel-like structures by mechanical stress and the addition of stromal supporting cells, namely, endothelial cells and MSCs [98]. After being fabricated, human myocardial tissues were transplanted onto athymia rat hearts; the grafts survived and contained human microvessels, which were perfused by the host coronary circulation [98]. In the near future, pulsatile 3D human myocardial tissues fabricated by human ESC/iPSC-derived cardiomyocytes could be used in clinical application.
ACKNOWLEDGMENTS We appreciate the useful comments and technical criticism of Dr. Norio Ueno (Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University). This work was supported by grants from Center of Excellence (COE) Program for the 21st Century, the Global COE Program, Multidisciplinary Education and Technology and Research Center for Regenerative Medicine (MERCREM), Innovation Center for Fusion of Advanced Technologies in the Special Coordination Funds for Promoting Science, and the High-Tech Research Center Program from the Ministry of Education, Culture, Sports Science, and Technology (MEXST), Japan; and the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP).
AUTHOR CONTRIBUTIONS Y.H., T.S.: conception and design, manuscript writing; M.Y.: conception and design, financial support, manuscript writing; T.O.: conception and design, final approval of manuscript.
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