Cardiac stem cell therapy: Current status and future prospect
Paracrine Effects of Cell Transplantation: Modifying Ventricular Remodeling in the Failing Heart

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Structural ventricular remodeling determines the clinical progression of heart failure and has emerged as an important target for the development of novel medical and surgical therapeutic strategies. Cell transplantation is an innovative biologic therapy that may restore myocardial structure and function in failing hearts. With current forms of cell transplant therapy, true myocardial regeneration has been limited. However, cell transplantation can predictably limit maladaptive ventricular remodeling through multiple synergistic paracrine mechanisms. Some of the paracrine factors released by transplanted cells have been defined. These paracrine signals may provide beneficial effects by stimulating angiogenesis, limiting matrix disruption, and preventing apoptosis. In addition, cell transplantation may induce mobilization and homing of endogenous repair cells to injured myocardium through paracrine signals. Paracrine mediators released from transplanted cells work through multiple, diverse, and interrelated molecular pathways resulting in synergistic effects on the remodeling process. Although true myocardial regeneration remains the ultimate goal of cell therapy, the anti-remodeling abilities of cell transplantation can be harnessed to complement our contemporary surgical approaches for patients with myocardial injury at risk of congestive heart failure.

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Background

In 1996, Li and colleagues provided the first evidence that cell transplantation improves cardiac structure and function after myocardial injury.3 Transplanted fetal cardiomyocytes formed a cardiac tissue that limited scar expansion and improved the systolic function of cryoinjured rat hearts. The field of cell transplantation for cardiovascular disease was ripe for discovery, and the potential to alter the remodeling process was recognized. Since fetal cells were of questionable clinical

Ventricular Remodeling and Progression of Heart Failure

In response to cardiac injury, a maladaptive process is triggered that progressively alters the size, shape, and function of the heart (structural cardiac remodeling).11, 12 The development of heart failure is associated with well-defined clinical, physiologic, and anatomical landmarks. Structural cardiac remodeling, particularly ventricular dilation, is the hallmark of congestive heart failure. Chamber dilation and wall thinning determines the clinical progression of heart failure and has

Molecular Mechanisms Underlying Cell Therapy

The evolving clinical reality that muscle cell transplantation for ischemic cardiomyopathy can limit chamber dilation and the progression of heart failure is overshadowed by a limited understanding of the molecular and cellular mechanisms underlying the beneficial effects of cell engraftment. An improved understanding of the host tissue response to cell implantation may optimize the development of this technique for its evolving therapeutic use and, in so doing, serve to improve our

Paracrine Effects on Angiogenesis

In animal models of myocardial ischemia, administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can improve the perfusion of the ischemic region by inducing angiogenesis.14 While many cytokines have angiogenic activity, the best studied are VEGF and FGF. However, angiogenesis is a complex process that involves numerous growth and signaling factors. Administration of high levels of VEGF or FGF alone can induce angiogenesis within ischemic tissues.

Paracrine Effects on Matrix Homeostasis

Once considered inert physical scaffolding, the extracellular matrix (ECM) is now widely appreciated as a dynamic signaling network that assembles and maintains groups of cells into functional tissues. The ECM can respond to environmental stimuli and tissue injury by altering its abundance, composition, and spatial organization with profound consequences on the structure and function of the tissues that it inhabits. After myocardial infarction, the ECM becomes dysfunctional. Cell to matrix

Paracrine Effects on Apoptosis

The overriding goal of cell therapy is to replace cells lost to injury and thereby repopulate the heart with functional contractile elements. We now understand that myocardial cells are continually lost in the failing heart, even when the inciting injury such as coronary ischemia has subsided. The myocardial capacity for cell renewal is limited and incapable of completely replacing these lost elements. Programmed cell death, known as apoptosis, is a key mediator of maladaptive structural

Paracrine Effects on Cell Recruitment and Endogenous Repair Mechanisms

The innate capacity of the heart to regenerate and repair after substantial injury is limited. However, circulating progenitor cells have been identified, and these stem cells may act as an endogenous repair mechanism. Resident stem cells within the heart have also been identified, and it is possible that cardiac stem cells have some endogenous repair capacity as well. Cell transplantation, particularly with stem cells, may act to trigger or enhance endogenous repair mechanisms. This protective

Conclusions

Cell transplantation offers the promise of cardiac regeneration. To date, the evidence for true myocardial regeneration with cell injection is limited. However, cell transplantation can predictably limit maladaptive ventricular remodeling through multiple synergistic paracrine mechanisms. While not the original aim for this novel therapy, the antiremodeling abilities of cell transplantation can be harnessed to complement our contemporary surgical approaches for patients with cardiac dysfunction

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    PWMF is a clinical investigator of the Alberta Heritage Foundation for Medical Research.

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