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Cardiac Stem Cell

(Scientific Review)

Summary: According to the CDC, heart disease causes the death of more than half a million Americans a year.[1] One of the contributing factors in the progression of heart failure is the loss of cardiomyocytes after myocardial infarction combined with the absence of an adequate endogenous repair mechanism. To date, heart transplantation would be the only effective way of curing heart failure. However, cell transplantation with stem cells has now surfaced as a potential therapy for heart failure. For more than twenty years there have been debates on whether or not the human heart is capable of regenerating new tissue after heart injury. Here we review recent laboratory findings that discuss the existence of Cardiac Stem Cells as a possible means of correcting damage to the heart by the regeneration of new cardiac tissue. We conclude the possibility of cardiac stem cells and, which if proven in the adult heart could be clinically useful for the treatment of heart disease.

Clinical Background: When the mammalian heart undergoes damage caused by heart disease, the activation of endogenous repair mechanisms occur. The mechanisms used by the heart to repair itself often result in the following: 1) removal of non-functional myocytes, 2) fibrosis, and/or 3) cardiac hypertrophy. [2, 3] While cell death is the process whereby non-functional myocytes are removed, fibrosis usually results from the death of cardiomyocytes. Cardiac hypertrophy, allows the heart to compensate for the loss of the dead myocytes. Together, these mechanisms are necessary and retain functions of the heart for a short period, However, after prolonged period these mechanisms can lead to extensive damage of the cardiomyocytes, and negative cycles of damage, repair, and death (Figure 1).

The negative cycle (Figure 1) becomes difficult to avoid in the adult heart because of the damage and loss of cardiomyocytes. Traditionally, it was thought that cardiomyocytes are generated during embryogenesis. Months after birth, cardiomyocytes stop dividing. Without the division of cardiac tissue the adult heart gradually becomes less functional. This is compounded by the endogenous repair mechanisms discussed above. A tissue- specific cardiac stem cell would potentially put an end to this negative cycle of damage.

Cardiac Stem Cell Defined:

Stem cells are undifferentiated cells that can proliferate, self-renew and differentiate into one or more types of specialized cells. [9] Cardiac stem cells can differentiate into the three major cell types of the myocardium: smooth muscle, endothelium and cardiomyocytes (Figure 2). Research strongly suggests that the heart maintains this reservoir of stem cells enabling the heart to make new cells when it is damaged. The cardiac stem cells are distinct from less primitive or progenitor cells that are istle 1 +.[5] Both cell populations divide and renew themselves, but the progenitor cells are committed to becoming heart cells, whereas the cardiac stem may be a more primitive cell having the potential to form several different cell types.

Evidence for the Existence of Cardiac Stem Cells:

Different studies and clinical trials have independently identified primitive cells from the adult heart that have the capability of dividing and developing into mature heart and vascular cells. These studies involve animal as well as heart obtained from subjects with various pathologies. Based on these studies, three types of cardiac stem cells have been identified, based on the markers shown in Table 1. [6] These surface antigens typically present in the hematopoietic stem cells of bone marrow, and have been identified on cardiac stem cells, independently or in combinations. Similar findings have been observed in the adult rat heart.

Researchers have found cells with stem cell phenotype in the tissues of patients with heart disease who were undergoing cardiac surgery. In aortic stenosis patients there was evidence of increased cardiac mass, which was the result of myocyte hypertrophy and hyperplasia. Hypertrophy is a normal process seen in the heart after damage; however hyperplasia the division of cells, must have resulted from the differentiation of primitive cells. [10] Cell clusters containing stem cells that were making the transition to myocyte precursors were found undergoing symmetrical division and generating asynchronously different progeny, therefore providing strong support for the existence of cardiac stem cells. [11]

Clinical Applications of Cardiac Stem Cells:

As discussed above cardiac stem cells have been shown to differentiate into endothelial cells, cardiomyocytes, and smooth muscle cells, thus making them an ideal candidate for repair of the damaged heart. Piero Anversa and his colleagues have identified pockets of stem cells in the interstices or spaces between muscle cells and the hearts of rats and noted these cells to be cardiac stem cells. In an experiment they conducted these stem cells were obtained from those areas in the hearts of the rats were cultured and injected into rats with damaged heart tissue. Seventy percent of the damaged myocardium was reconstituted within 20 days. [10] In other in vivo studies, the cardiac stem cells implanted directly into the infarcted ventricle as well as those mobilized from sites of storage within the heart migrated to the dead myocardium, engrafted, underwent multilineage commitment, and promoted cardiac regeneration, thus providing proof for the existence of cardiac stem cells.[11]

Non-cardiac stem cell transplantation into a diseased heart has been reported to induce the activation of paracrine affects. Unidentified molecules can be released from stem cells to cause the differentiation of resident cardiac stem cells. The effect may also inhibit apoptosis of cardiomyocytes.

Three sites have been reported as regions to introduce cardiac stem cells within the injured heart: 1) coronary artery leading to that site of damage, 2) myocardium with the aid of catheters and, 3) directly into the site of damage during open heart surgery. In order for cardiac stem cells to be useful in repairing damaged heart tissue in humans, an effective method of isolating, growing, and purifying are needed. Thus, further research studies are required. [12]

Conclusion:

Heart disease remains the leading cause of mortality and morbidity in industrialized countries. [11] Current approaches targeting blood flow and ventricular remodeling are discouraging due to the inability to repair the infarcted myocardium with new cardiac tissue. However through the advent of animal models and human clinical trials it has been shown that different groups of stem cells, particularly the cardiac stem cell, participate in cardiac regeneration, with concurrent improvement in cardiac function. The stem cell of primary focus in the regeneration of damaged cardiac tissue is this cardiac stem cell that resides within the heart muscle itself. [11]

Although there is continuous research being done to confirm the existence of cardiac stem cells there are other stem cells currently being considered for the treatment of heart disease. The different stem cells that are being investigated include, but are not limited to embryonic stem cells, hematopoietic stem cells, and mesenchymal stem cells. The disadvantages with the use of these other stem cells include the possibility of rejection by the recipients' immune system because of their allogenic origin, the ethical issues posed with their isolation and use, and the possibility of teratoma formation when injected undifferentiated into hosts. It is these disadvantages that will be bypassed with the use of cardiac stem cells.

Many strides have been made and continue regarding an understanding of cardiac stem cells. Researchers appear to have identified cardiac stem cells in the heart, and believe to have identified their anatomical locations within the heart. Current studies are ongoing to determine efficient methods to have the cardiac stem cells expand. This could lead to indepth understanding of the cardiac stem cells, at the molecular and cellular levels. Animal models and randomized, double-blinded human clinical trials with cardiac stem cells have been, and will be imperative to gather more safe and efficient data that elucidate the underlying mechanism of cardiac regeneration. Through the use of cardiac stem cells in regenerative medicine there could be an end to patients succumbing to heart disease.

Acknowledgements

This review was prepared by the following graduate students in the Stem Cell Biology Class, Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey: Comfort Amoh-Tonto, Walter Alzate, Nadin Exantus, and Nora Gashi (in alphabetical order).

Teaching Assistant: Raghav G. Murthy

The review was edited by two stem cell biologists.