Sci. Aging Knowl. Environ., 2 July 2003
Vol. 2003, Issue 26, p. pe17
[DOI: 10.1126/sageke.2003.26.pe17]

PERSPECTIVES

Adult Cardiac Stem Cells--Where Do We Go from Here?

Jay M. Edelberg, Munira Xaymardan, Shahin Rafii, and Mun K. Hong

The authors are in the Division of Cardiology, Department of Medicine, at the Weill Medical College of Cornell University, New York, NY 10021, USA. E-mail: jme2002{at}med.cornell.edu (J.M.E.)

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/26/pe17

Key Words: ischemic heart disease • cardiovascular disease • stem cells • bone marrow

Introduction

Stem cell therapies offer the possibility of novel disease treatments that use cells derived from the patient's own body (autologous treatments) (see Edelberg Perspective). Previous studies have demonstrated the potential of stem cells isolated from patients to give rise to both endothelial progenitor cells, which develop into blood vessels, and cardiac muscle cells (myocytes) (1-5). Such cells are potentially quite useful in the treatment of cardiovascular diseases, because they can increase the heart's vascular supply (useful for the treatment of coronary artery disease) or provide cardiac muscle cells (of value for the treatment of congestive heart failure). On the basis of such findings, clinical approaches that employ direct cell transplantation procedures are currently being tested in limited sets of patients with ischemic heart disease, which is caused by arterial blockage and a resulting lack of oxygen and results in cardiac cell death and dysfunction in the compromised heart tissue (6, 7). The eventual widespread translation of stem cell technologies into clinical practice, however, will likely be based on treatments with drugs (pharmacotherapies) that enhance the potential of endogenous stem cells to develop into cardiac cells (the so-called cardioplastic potential) for the treatment and possible prevention of cardiovascular disease.

Cardioplastic Potential of Adult Stem Cells

Stem cell-based studies aimed at augmenting myocardial performance have been conducted in rodent models of acute coronary occlusion. In these rodents, the blood supply to the heart is blocked, resulting in the death of myocytes and scarring of the cardiac tissue to yield impaired cardiac function. Transplanted stem cells have been used to ameliorate this injury process by regenerating cardiac myocytes and replenishing the vascular supply in the damaged heart. Previously, a wide range of cell types has been used for transplantation, including embryonic, fetal, and neonatal cardiac myocytes, as well as skeletal myoblasts (8-13). Advances in adult bone marrow stem cell therapy might now provide alternative cell sources for treating cardiovascular diseases in humans.

Adult bone marrow contains multipotent mesenchymal stem cells, which are derived from the somatic mesoderm and give rise to arrays of specific cells, including skeletal myoctyes (14), central and peripheral neurons (15, 16), and hepatic cells (17). These cells are involved in the self-maintenance and repair of various mesenchymal tissues. Bone marrow-derived cardiac myocytes have been shown to populate rodent heart tissue after myocardial infarction (4) or cardiac transplantation (18). Moreover, preclinical studies have shown that the injection of bone marrow cells directly into the myocardium enables these cells to differentiate into cardiac myocytes, smooth muscle cells, and endothelial cells. These transformations can lead to regeneration of the myocardium and improvement of cardiac function (3, 19). Similarly, mobilization of bone marrow stem cells and lineage-committed progenitor cells can promote the generation of bone marrow-derived cardiac myocytes and endothelial progenitor cells (20, 21). These observations suggest that strategies directed at the mobilization and homing of specific stem cells to the heart could limit the impact of cardiovascular diseases.

Developing Clinical Stem Cell-Based Therapies to Treat Cardiovascular Disease

Recently described clinical trials pursuing the translation of cardiac stem cell approaches to human patients have employed direct cell transplantation strategies. Strauer et al. reported the first clinical investigation of autologous bone marrow cell infusion via intracoronary injection in 10 patients after acute myocardial infarction (6). These patients also received conventional angioplasty treatment, whereas a control study population of 10 additional myocardial infarction patients was treated with angioplasty alone. Three months after injection, the investigators found significant improvement in cardiac function in those receiving bone marrow cells as compared with the control group. The authors suggest that the bone marrow cells may have induced angiogenesis (the development of new capillaries) and cardiomyogenesis, which might have contributed to the beneficial effects of autologous bone marrow transplantation. However, because proangiogenic hematopoietic cells that can mediate immune functions were also injected in this study, it remains to be determined whether the improvement was caused by the vasodilatory effect of such inflammatory cells or true angiomyogenesis, as well as how long the benefit will last.

Assmus and co-workers have studied the feasibility and safety of transplanting either autologous bone marrow-derived cells or circulating blood-derived progenitor cells in cardiac patients (7). Cells were transferred into the diseased (blocked) coronary artery approximately 4 days after the artery was successfully reopened in a surgical procedure. The bone marrow cells were obtained on the day of the intracoronary infusion and consisted mainly of mononuclear cells (purified to remove red blood cells and platelets). The peripheral progenitor cells were obtained 3 days before infusion, and the mononuclear cells were cultured ex vivo for 3 days before intracoronary infusion. Two groups of patients were treated, each with one of the two cell types (bone marrow cells, n = 9 patients; circulating precursor cells, n = 11 patients). Both groups received cells injected into the central lumen of an angioplasty balloon in the infarct-related artery. The patients' progress was then followed for 4 months. Compared with nonrandomized, but matched, patients without intracoronary infusion of the progenitor cells, the treated patients exhibited a significant improvement in global left ventricular contractile function, regional heart wall motion in the area supplied by the occluded coronary artery, and myocardial viability at 4 months, as assessed by a combination of invasive and noninvasive techniques, including positron emission tomography (a procedure that can detect viable cardiac muscle on the basis of its uptake of fluorolabeled glucose). There were no differences between patients receiving bone marrow and those receiving peripheral progenitor cell groups in this small study. There were no inflammatory reactions, as measured by leukocyte blood count or serum C-reactive protein levels, nor were there any arrhythmic events up to 4 months after the procedure. The authors hypothesize that the benefit was potentially a result of neovascularization that could favorably influence left ventricular remodeling. However, as in all these studies, hematopoietic and nonangiomyogenic cells were also transplanted. Thus, there is the possibility that these other cell types could generate an aberrant tissue or dysintegrity of the cardiac myocardium. Therefore, whole bone marrow or circulating mononuclear cells should be used with extreme caution and long-term close clinical monitoring.

Limitation of Cell Transplantation in Cardiovascular Treatments

The applicability of present cell transplantation approaches may be limited to a narrow subgroup in the extensive population with coronary heart disease. One uncertainty derives from the small sample sizes and limited follow-up periods in the pilot studies described above. Furthermore, the study populations included patients with no previous coronary heart disease, who were presenting with their first acute coronary occlusions. Thus, cardiac function was relatively preserved in both the treated and control patients (6, 7). It remains unclear whether similar results could be expected in patients with previous myocardial infarctions and significant cardiac muscle dysfunction. Moreover, whether the same approach would be beneficial in patients with nonischemic origins of the cardiac pathology, as well as in those with limited bone marrow reserves, such as older persons (22), are also unknown and are important issues to investigate.

The application of cellular transplantation as a cardiovascular therapy is also directly limited by the nature of the procedure. The significant costs associated with cell isolation and cardiac intervention may confine present approaches to individuals undergoing cardiac catheterization or coronary surgery. Yet, the widespread translation of stem cell technology might be achieved by developing strategies to enhance the cardioplastic potential of the bone marrow cells within individuals who have or are at risk for cardiovascular disease, and by avoiding dependence on techniques involving cell transplantation.

Pharmacotherapies

Pharmacotherapies aimed at augmenting the natural mobilization of endogenous bone marrow-derived cardiovascular progenitor cells, a process that occurs in response to injury caused by cardiovascular diseases, have the potential to diminish the risk of myocardial injury in some individuals. Recent clinical studies by Hill and colleagues have demonstrated that individuals with impaired levels and function of endothelial precursor cells have an increased incidence of adverse cardiac events (23). This result suggests that these cells might have cardioprotective actions, such as the ability to enhance the development of new vascular supplies to potentially compromised tissue. Indeed, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are used to lower blood lipid levels and are conventionally referred to as statins, may produce some benefits through increased endothelial progenitor cell mobilization. Vasa and colleagues studied the effect of high-dose atorvastatin therapy on the number and function of circulating endothelial progenitor cells in patients with documented coronary artery disease and stable angina (chest pain that occurs because of an inadequate supply of oxygen to the cardiac muscle). These researchers found a greater than threefold increase in the levels of endothelial progenitor cells after 4 weeks of treatment (24). The treatment appeared to affect endothelial progenitor cells directly, increasing their migratory capacity in vitro. Indeed, the actions of statin therapy appeared to be specific to endothelial progenitor cells, because this treatment did not induce the mobilization of other bone marrow precursor cells.

Effective cardiovascular stem cell therapy through pharmacological means may require more than the mobilization of endothelial progenitor cells. For example, previous studies have demonstrated that exogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes the generation of bone marrow-derived cardiac myocytes and results in improved cardiac function after myocardial infarction (20). In clinical trials, Seiler and others studied the benefits of GM-CSF therapy in patients with extensive coronary artery disease that was not amenable to coronary artery bypass surgery. Patients that were able to undergo angioplasty in at least one vessel were randomized either to intracoronary injection of GM-CSF, followed by subcutaneous treatments every other day for 2 weeks, or to a placebo (25). At the end of the short study period, there was a significant improvement in myocardial blood flow and clinical symptoms in the experimental versus the placebo group.

The disadvantage of these indirect approaches is that the increase in circulating progenitor cells might not result in selective homing to the damaged region of the cardiovascular system. Pharmacological mobilization of cardiovascular stem cells, including endothelial progenitor cells, could increase the risk of stimulating in situ tumor growth, as well as angiogenic blood vessel growth at other pathological sites induced by chronic inflammation or infection. Moreover, an integrated strategy requires the promotion of stem cell function in cardiovascular tissue. Indeed, results of recent animal model studies have suggested that endothelial progenitor cells derived from the bone marrow of elderly people may have impaired activity and thus demonstrate the need for approaches to enhance endogenous stem cell function in those with the greatest risk of developing cardiovascular disease (18) (see Edelberg Perspective).

Future Developments in Cardiac Stem Cell Approaches

Fulfilling the promise of stem cell therapies for the treatment and possible prevention of cardiovascular disease requires advancements in both cell-based strategies and the development of specific pharmacological reagents. Autologous stem cell transplantation studies require placebo-controlled trials coupled with rigorous data analysis to determine the benefits of these approaches. On the basis of our relatively limited experience with cardiac stem cell approaches, these trials may be suited more as an adjunctive therapy rather than as a replacement for the proven and existing revascularization options, unless the patients are felt to have no other choices. The potential role of sources of bone marrow other than the patient will require extensive preclinical assessment.

The development of pharmacological methods to promote the action of cardiac stem cells requires further basic research. The hematopoietic system may provide important clues into the biology of cardiovascular stem cells (for a discussion of hematopoiesis, see the Fuller Perspective). Indeed, the molecular mechanisms governing the mobilization and homing of cardiovascular stem and precursor cells into the heart may parallel hematopoietic stem cell biology, with the production and targeting of specific cell types to sites of inflammation and injury. Using the immune cell paradigm as a basis, future studies could be designed to identify the specific factors that induce progenitors of endothelial cells and cardiac myocytes, as well as the adhesion molecules that mediate the local homing of the progenitor cells to cardiovascular tissues. The identification of such molecules, in conjunction with advances in current cardiac stem cell technologies, may allow the development of biological approaches that can be specifically tailored to provide cardioprotection, without enhancing pathology in noncardiac tissue.


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Citation: J. M. Edelberg, M. Xaymardan, S. Rafii, M. K. Hong, Adult Cardiac Stem Cells--Where Do We Go from Here? Sci. SAGE KE 2003, pe17 (2 July 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/26/pe17








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