Prepare Cells to Repair the Heart: Mesenchymal Stem Cells for the Treatment of Heart Failure

Heart failure is one of the most important cardiovascular diseases, with high mortality, and invasive treatment such as mechanical circulatory support and cardiac transplantation is sometimes required for severe heart failure. Therefore, the development of less invasive and more effective therapeutic strategies is desired. Cell therapy is attracting growing interest as a new approach for the treatment of heart failure. As a cell source, various kinds of stem/progenitor cells such as bone marrow cells, endothelial progenitor cells, mesenchymal stem cells (MSC) and cardiac stem cells have been investigated for their efficacy and safety. Especially, bone marrow-derived MSC possess multipotency and can be easily expanded in culture, and are thus an attractive therapeutic tool for heart failure. Recent studies have revealed the underlying mechanisms of MSC in cardiac repair: MSC not only differentiate into specific cell types such as cardiomyocytes and vascular endothelial cells, but also secrete a variety of paracrine angiogenic and cytoprotective factors. It has also been suggested that endogenous MSC as well as exogeReceived: March 7, 2007 Accepted: March 19, 2007 Published online: April 25, 2007 Nephrology American Journal of Noritoshi Nagaya, MD, PhD Fujishirodai 5-7-1, Suita Osaka 565-8565 (Japan) Tel. +81 6 6833 5012, Fax +81 6 6833 9865 E-Mail [email protected] © 2007 S. Karger AG, Basel 0250–8095/07/0273–0301$23.50/0 Accessible online at: www.karger.com/ajn Ohnishi/Nagaya Am J Nephrol 2007;27:301–307 302 ical circulatory support, continuous inotropic infusion, or cardiac transplantation [7–9] . Therefore, there is a need to develop more effective, less invasive therapeutic strategies for heart failure. Cell therapy for heart failure has the potential to restore cardiac function by inducing neovascularization, and regenerating and protecting cardiomyocytes [4] . Bone marrow-derived mononuclear cells (MNC) and endothelial progenitor cells (EPC) have been applied for ischemic cardiovascular disease in human studies [10– 12] . Recently, mesenchymal stem cells (MSC), a subpopulation of MNC, have emerged as a new therapeutic cell source because they possess multipotency and can be easily expanded in culture [13] . This article reviews cell therapy for heart failure, and focuses on the therapeutic potential of MSC for heart failure. Cell Sources for Cardiac Repair Several kinds of cells have the potential to be applied for cardiac repair; embryonic stem (ES) cells and somatic stem or progenitor cells (skeletal myoblasts, MNC, MSC, EPC, cardiac stem cells) ( table 1 ). Because ethical problems may limit the immediate application of ES cells, we herein describe the features and characteristics of somatic cells. Skeletal myoblasts, which are derived from cultured satellite cells, were the first to be tested in clinical trials. Satellite cells are muscle progenitor cells which normally mediate the regeneration of skeletal muscle [14] . They can be easily expanded in culture in an undifferentiated state, and are highly resistant to tissue ischemia. In vivo studies have demonstrated that the administration of myoblasts improved cardiac function [15–18] . However, in early clinical studies, myoblast transplantation was associated with sustained ventricular tachycardia [19] , which requires defibrillator implantation and/or amiodarone therapy. Bone marrow cells include several types of stem/progenitor cells such as hematopoietic stem cells and MSC, although the vast majority of bone marrow cells are hematopoietic cells [20, 21] . Because of the extensive clinical experience in bone marrow transplantation for hematological diseases over the past decades and the fact that large numbers of bone marrow cells can be easily obtained, the study of bone marrow cell transplantation for treating heart failure has moved quickly from small animals to human studies. Direct or intracoronary injection of bone marrow cells appears to be safe and beneficial for the treatment of acute myocardial infarction and chronic ischemic heart disease [11, 22–25] . However, it is not clear whether the optimal bone marrow cell population for transplantation is hematopoietic stem cells, MSC, or abundant committed cells. The major goal of studies using bone marrow cells will be to identify the most effective cell population from these complex mixtures. EPC, a rare subpopulation of bone marrow cells with a similar phenotype and function to those of fetal angioblasts, have been demonstrated to be involved in neovascularization after myocardial infarction [26] . In addition, there was a significant reduction in collagen deposition and apoptosis of cardiomyocytes and an improvement in cardiac function. It has been demonstrated that granulocyte colony-stimulating factor (GCSF) and stem cell factor can mobilize EPC [27, 28] . Clinical trials studying the ability of G-CSF to mobilize stem/progenitor cells in patients with coronary artery disease did not reach a conclusion on efficacy, while concerns have been raised on safety in relation to arterial restenosis and plaque destabilization. HMG-CoA reductase inhibitors [29] , estrogens [30] , exercise [31] , and nonsmoking [32] are more practical than growth factor or chemokine administration to enhance the number of circulating EPC in patients. Currently, clinical trials of EPC therapy for neovascularization and myocardial reEase of harvest Expandability Differentiation into cardiomyocytes Ethical issues Arrhythmogenesis Embryonic stem cells √ √ √ Cardiomyocytes √ √ Skeletal myoblasts √ √ √ √ Cardiac stem cells √ √ Endothelial progenitor cells √ √ Mononuclear cells √ Mesenchymal stem cells √ √ √ Table 1. Characteristics of cells used for the treatment of heart failure