Summary:
Heart disease remains one of the most prevalent disorders in the world.  In the United States, there are 7.1 million people living with myocardial infarction and another 4.9 million people living with congestive heart failure (1).  Even though there have been significant advances in treatment of heart failure, occurrences and related deaths continue to increase; data indicates that 20% of those diagnosed with congestive heart failure will die within 12 months (1). Therefore, the medical community is exploring the option of stem cell-based therapy in cardiac repair. The discovery of the cardiac stem cell has expanded the potential for clinical utilization of stem cells to regenerate functional myocardial tissue after damage.

Definition of Cardiac Stem Cell:
The discovery of the cardiac stem cell revolutionized the field of cardiac biology by undermining the previously accepted notion that the mammalian adult heart is a post-mitotic organ lacking self-renewal or regenerative potential (6).  Cardiac stem cells have the properties of self-renewal, clonogenicity, and multipotency; they are capable of differentiating into cardiomyocytes, smooth muscle cells, and endothelial cells (Figure 1) (4).  Cardiac stem cells are identified in both human and murine models based on the following cell surface antigens: c-kit, Sca-1, and MDR1 (4).  However, Cindy Martin and her colleagues identified side population (SP) cells, which have the capacity to self-renew and differentiate into cardiac cells in the adult heart, based on the expression of Abcg2, an ATP-binding cassette transporter, instead of identification via cell surface markers (1,11).  Many in the scientific community believe cardiac stem cells to be essential in cardiac homeostasis and during incidences of acute stress.  Research found increased myocyte formation as a result of cardiac stem cell differentiation in patients with chronic aortic stenosis (5). Since cardiac stem cells have the ability to differentiate into the three essential cell types which compose functional myocardium tissue, they have vast potential in cardiac repair therapies.

Relevant Pathology:
Occlusion of coronary arteries and acute myocardial ischemia induces an extensive death of myocytes and vascular structures in the mammalian heart (8).  Substantial death of myocytes or death to heart tissue following myocardial infarction can lead to the heart failure, which correlates with reduced life expectancy (7,9).  Following acute myocardial infarction, complications surmount as damaged heart tissue is steadily replaced by fibrotic noncontractile cells, and this process progresses cardiac tissue dysfunction that results from extensive myocyte death (7).  Even though there have been significant advances in diagnostic technology and treatment of heart failure, cardiac dysfunction following myocardial infarction remains one of the most pervasive cardiovascular disorders (7).  Hence, cardiac stem cells may play a crucial role in the development of therapeutic approaches to improve damaged and dysfunctional heart tissue following myocardial infarction. 

Clinical Application:
In order to determine the clinical efficacy of cardiac stem cells in myocardial regeneration, the mechanism through which stem cells enable cardiac repair must be fully understood.  Prior to the discovery of cardiac stem cells, prevailing stem cell based-therapies involved transplanting bone marrow cells into the region of damage and achieving regeneration via the differentiation of these cells into functional myocardial tissue (1,2).  After the identification of the cardiac stem cell, therapies can now begin to focus on research which supports that expansion of inherent cardiac stem cell niches confers regenerative capabilities to infarcted myocardium (1,4).  With the discovery of this intrinsic potential in cardiac tissue, research and therapies can now be aimed at finding and utilizing factors which facilitate regeneration of myocardial tissue via more noninvasive procedures.  A recent study found evidence that the hormone oxytocin may induce differentiation of cardiac stem cells to cardiomyoctes through a nitric oxide signaling pathway (13).

Also, cardiac stem cells can be extracted from patients and expanded significantly ex vivo, and then transplanted into the region of damage or infarction in order to aid regeneration (1).  Presently, there are two prevalent approaches for cardiac stem cell transplantation: a transvascular approach and a direct insertion into the ventricular wall (Figure 2) (10).  The transvascular approach, which is most suitable for patients with acute myocardial infarction and reperfused myocardium, involves infusing cardiac stem cells directly into the coronary arteries (10).  Once these stem cells are in the coronary arteries, they would home to the site of injury due to the activation of specific adhesion molecules and chemokines (10,12).  However, the transvascular approach would not be suitable in patients with severe occlusion within the vessels of an injured region, and in such a case, a direct injection into the ventricular wall remains the only feasible approach (10).  A direct injection of cardiac stem cells can be possible during open heart surgery, during which these cells can be inserted either directly into the ventricle or into one of the cardiac veins, depending on the site and nature of injury.  Although these procedures may offer great therapeutic value, there may also be some potential complications.  Transplanted cardiac stem cells may harm the patient if they migrate to other regions of the body, and in addition, complications can arise if the transplanted stem cells differentiate into undesired cell types.  Therefore, many concerns need to be addressed before cardiac stem cells can be transplanted into patients with myocardial infarction.

Limitations to Cardiac Stem Cell Applications
Although cardiac stem cells have great therapeutic potential, there are many challenges regarding their applications in the clinical setting that must to be addressed.  Thus far, there have been no clinical trails performed using human cardiac stem cells, and therefore, further research must be performed before these cells become feasible options for cardiac repair.  Some of the problems encountered with the use of other exogenous stem cells in cardiac repair are arrhythmias, restenosis, accelerated atherosclerosis, coronary obstruction, and abnormal cellular differentiation (10).  Hence, these same problems must be confronted with respect to cardiac stem cells before clinical trails may begin.  In addition, cardiac stem cells exist in limited quantities and the difficulties associated with ex vivo separation and expansion must also be addressed.  Consequently, researchers and clinicians must surmount many challenges before cardiac stem cells become commonplace in clinical medicine.

Conclusion:
Cardiovascular disease remains the leading cause of death in the United Sates and Europe despite advances in diagnostic technology and treatment (10).  As research indicates, cardiac stem cells have immense potential in regenerative medicine and may be capable of addressing the shortcomings of traditional therapeutic approaches.  However, before cardiac stem cells become a viable option in treating cardiac dysfunction, many issues regarding their efficacy and safety must be addressed. Recently, the National Heart, Lung, and Blood Institute (NHLBI) has awarded funding for clinical trails of cardiac stem cells to the Specialized Center for Cell-Based Therapy (1). The future awaits for the discovery of innovative therapeutic approaches to address cardiovascular diseases.

References

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