Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900 except 1918. Heart attacks and congestive heart failure remain among the Nation’s most prominent health challenges despite many breakthroughs in cardiovascular medicine. Despite advances in surgical procedures, mechanical assistance devices, drug therapy, and organ transplantation, more than half of patients with congestive heart failure die within five years of initial diagnosis. The restoration of function to the damaged heart remains a formidable challenge. Recent research is providing early evidence that adult and embryonic stem cells may be able to replace damaged heart muscle cells and establish new blood vessels to supply them.
However, endogenous repair mechanisms, including the proliferation of cardiomyocytes under conditions of severe blood vessel stress or vessel formation and tissue generation via the migration of bone-marrow-derived stem cells to the site of damage, are in themselves insufficient to restore lost heart muscle tissue (myocardium) or cardiac function.
The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of embryonic and adult-derived stem cells for cardiac repair. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells, mesenchymal stem cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells, and umbilical cord blood cells, have been investigated to varying extents as possible sources for regenerating damaged myocardium. Preliminary clinical data for many of these cell types have also been gathered in selected patient populations.
However, clinical trials to date using stem cells to repair damaged cardiac tissue vary in terms of the condition being treated, the method of cell delivery, and the primary outcome measured by the study, thus hampering direct comparisons between trials. The transplanted cells may be autologous (i.e., derived from the person on whom they are used) or allogeneic. In preliminary clinical studies, researchers have used several approaches to deliver stem cells. Common approaches include intravenous injection and direct infusion into the coronary arteries. However, these strategies may be of limited benefit to those who have poor circulation, and stem cells are often injected directly into the ventricular wall of these patients (endomyocardial injection).
Embryonic and adult stem cells have been investigated to regenerate damaged myocardial tissue in animal models and in a limited number of clinical studies. Mouse and human ES cells have been shown to differentiate spontaneously to form endothelial and smooth muscle cells in vitro and in vivo, and human ES cells differentiate into myocytes with the structural and functional properties of cardiomyocytes. Any differentiated cells that would be used to regenerate heart tissue must be purified before transplantation can be considered. If injected regenerative cells are accidentally contaminated with undifferentiated ES cells, a tumor could possibly form as a result of the cell transplant.
While skeletal myoblasts (SMs) are committed progenitors of skeletal muscle cells, their autologous origin, high proliferative potential, commitment to a myogenic lineage, and resistance to ischemia promoted their use as the first stem cell type to be explored extensively for cardiac application. Studies in rats and humans have demonstrated that these cells can repopulate scar tissue and improve left ventricular function following transplantation. To date, the safety and feasibility of transplanting SM cells have been explored in a series of small studies enrolling a collective total of nearly 100 patients. Phase II studies of skeletal myoblast therapy are presently underway.
Researchers have investigated the potential of human adult bone marrow as a source of stem cells for cardiac repair. Adult bone marrow contains several stem cell populations, including hematopoietic stem cells, endothelial progenitor cells, and mesenchymal stem cells; successful application of these cells usually necessitates isolating a particular cell type on the basis of its’ unique cell-surface receptors. In the past several years, the transplantation of bone marrow mononuclear cells (BMMNCs), a mixed population of blood and cells that includes stem and progenitor cells, has been explored in more patients and clinical studies of cardiac repair than any other type of stem cell.
Mesenchymal stem cells (MSCs) are precursors of non-hematopoietic tissues (e.g., muscle, bone, tendons, ligaments, adipose tissue, and fibroblasts) that are obtained relatively easily from autologous bone marrow. One advantage of using these cells in human studies is their low immunogenicity. Scientists can culture them under special conditions to differentiate them into cells that resemble cardiac myocytes. MSCs differentiate into endothelial cells when cultured with vascular endothelial growth factor and cardiomyogenic (CMG) cells when treated with the dna-demethylating agent, 5-azacytidine. More important, MSCs can differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart following myocardial infarct (MI) or non-injury in pig, mouse, or rat models. Additionally, the ability of MSCs to restore functionality may be enhanced by the simultaneous transplantation of other stem cell types. Clinical trials are currently underway to investigate the application of allogeneic and autologous MSCs for acute MI and myocardial ischemia, respectively.
Recent evidence suggests that the heart contains a small population of endogenous stem cells that most likely facilitate minor repair and turnover-mediated cell replacement. These cells have been isolated and characterized in mouse, rat, and human tissues. The cells can be harvested in limited quantity from human endomyocardial biopsy specimens and can be injected into the site of infarction to promote cardiomyocyte formation and improvements in systolic function. Their potential as a convenient resource for autologous stem cell therapy has led the National Heart, Lung, and Blood Institute to fund forthcoming clinical trials that will explore the use of cardiac stem cells for myocardial regeneration.
Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that are recruited into the peripheral blood in response to tissue ischemia. EPCs are precursor cells that express some cell-surface markers characteristic of mature endothelium and some of hematopoietic cells. Following a heart attack, intravenously injected EPCs home to the damaged region within 48 hours. The new vascularization induced by these cells prevents cardiomyocyte apoptosis (programmed cell death) and LV remodeling, thereby preserving ventricular function. No change has been observed in non-infarcted regions upon EPC administration. Clinical trials are currently underway to assess EPC therapy for growing new blood vessels and regenerating myocardium.
Several other cell populations, including umbilical cord blood (UCB) stem cells, fibroblasts, and peripheral blood CD34+ cells, have potential therapeutic uses for regenerating cardiac tissue. Although these cell types have not been investigated in clinical trials of heart disease, preliminary studies in animal models indicate several potential applications in humans. Autologous fibroblasts offer a different strategy to combat myocardial damage by replacing scar tissue with a more elastic, muscle-like tissue and inhibiting host matrix degradation.
