ABSTRACT
The human heart, which consists of a pair of left and right atriums and a pair of left and right ventricles, provides continuous blood circulation for supplying oxygen and nutrients to the whole body and sending carbon dioxide to the lungs by its strong mechanical pumping ability [1, 2]. The coronary artery, which runs elaborately around the heart, supplies oxygen and nutrients to the heart muscle, and the blood flow is essential for keeping heart tissue healthy. Heart tissue consists of many beating cardiomyocytes, which are the origin of the contractility of heart muscle. On the other hand, it has been known that more than half of cardiac cells are constituted of noncardiomyocytes, namely, (1) fibroblasts, (2) endothelial cells (ECs), and (3) smooth muscle cells (SMCs) [3-5]. Fibroblasts play a role in synthesizing and maintaining the mechanical scaffold for cardiomyocytes. ECs and SMCs constitute blood vessels that supply
oxygen and nutrients to cardiac cells, including cardiomyocytes and fibroblasts. Heart disease is the leading major cause of morbidity and mortality, especially in industrialized countries [6-8]. Infarction of the coronary artery, which is caused by several reasons, leads to the necrosis and loss of cardiac cells due to poor oxygen and nutrient supply. The myocardial necrosis progresses sequentially ischemic heart disease, which is found to show a phenomenon known as negative cardiac tissue remodeling, which is (1) left ventricular wall thinning in the infarction area, (2) ventricular chamber dilatation, (3) compensatory hypertrophy of the noninfarcted portion of the heart, and (4) heart tissue fibrosis [9, 10]. The remodeling decreases heart function and may induce lethal heart disease and arrhythmia [11, 12]. Dilated cardiomyopathy (DCM) is a heart disease characterized by ventricular (sometimes atrial) dilation, with reduced wall thickness, and finally leads to varying degrees of impaired systolic function [13, 14]. It is thought that DCM is caused by several reasons, namely, (1) electrolyte abnormality, (2) endocrine abnormality, (3) hypertension, (4) infection, and (5) ischemia, and familial DCM is also known [15]. Inhibition and/or improvement of the negative remodeling induces the improvement of cardiac performances. The following therapies for curing heart disease, including ischemic heart disease and DCM, have been performed clinically: (1) drug therapy (cardiac unloading by antihypertension, anticardiac remodeling, antiarrhythmia, etc.), (2) surgical therapy (coronary artery bypass graft surgery, surgical ventricular restoration, heart transplantation, etc.), (3) catheter-based therapy (balloon catheter, stent placement, ablation, etc.), and (4) medical device-based therapy (ventricular assist devices, cardiac pacemaker, etc.) [16-34]. Although these therapies markedly increase the survival rate of various patients, the mortality still remains high at present. Some therapies have several problems, namely, side effects (adverse effects), the necessity of special techniques, repeated therapy, immune rejection, donor shortage, infection, thrombi, etc. Many investigators have been making untiring efforts to solve the problems. Conventional therapies cannot restore the damaged myocardium, and at present, there is no therapy for patients with severe heart disease, other than heart transplantation. Recently, regenerative therapy has attracted increasing attention as an alternative therapy for heart transplantation (Fig. 1.1). Cytokine therapy for repairing
a damaged myocardium using angiogenesis-related growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), and hematopoietic cytokines, including granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), has been performed clinically [35-39]. The injection of angiogenesis-related cytokines is expected to promote the development of novel and supplemental collateral blood vessels, which can function as the “bypass” of an infarcted coronary artery. Hematopoietic cytokines are expected to regenerate a damaged myocardium via the mobilization of bone marrow-derived stem cells. On the other hand, for more effective therapy, cell-based regenerative therapy has also been started. Cell injection therapies using autologous cells, including skeletal myoblasts, cardiac stem cells, and bone marrow-and peripheral blood-derived cells, have been performed clinically and have shown modest improvements of cardiac functions in some clinical trials [40-46]. For overcoming the drawbacks of the direct injection of dissociated cells, scaffold-based myocardial tissue engineering has been appeared as a second-generation cell therapy [47-55]. On the other hand, “cell sheet
Cell therapy
Direct Injection
Cytokine therapy
Tissue Engineering
Figure 1.1 Regenerative therapy for heart disease.
