Utilization of stem cells to replace cardiac tissue destroyed during ischemic insult holds promise for improving cardiac function and reducing the incidence of heart failure. The need for such a promising intervention is paramount as the prevalence of heart failure continues to increase.1 Furthermore, despite continuing research, and the development of technological and drug-based interventions, mortality rates remain constant.2 A person with heart failure has a greater than 50% probability of dying of the disease within 8 years of the original diagnosis.1 The prognosis could be improved by replacing dead and injured cardiomyocytes and improving myocardial blood supply. Theoretically, stem cells directed to infiltrate damaged tissue and differentiate into functional muscle cells and blood vessels would permanently improve heart function and prognosis. The following 3 review articles provide an introduction to stem cells, describe the use of stem cells in cardiac repair, and explain bioengineering approaches in stem cell therapy.
Recent research has focused on harnessing the potential of stem cells to differentiate into heart and vascular tissue. However, to translate basic stem cell research into therapeutic reality, many questions require answers. Some of these questions include the following: Which type of "stem" cell can best differentiate into cardiac muscle and vascular cells? What factors are necessary to induce differentiation of these stem cells into cardiomyocytes, endothelial cells, or vascular smooth muscle cells? How can these cells be delivered to injured myocardial tissue? Can the replacement cells integrate functionally with cells that are present? For example, can replacement, differentiated stem cells become electrically coupled with each other and to the remaining healthy cardiac tissue? How can the cells be convinced to stay where they are needed? How long will replacement cells last and continue to be functional? Can at-risk patients donate their own cells such that appropriate cell types can be isolated, propagated, and banked for use in the case of myocardial infarction?
The first article in the series, "Introduction to Stem Cell Therapy," updates the reader's basic understanding of what stem cells are and how they are best classified. In this article, we find that the terms embryonic and adult stem cell are a less-than-satisfactory classification and that stem cells are better defined as pluripotent or multipotent. Sources of these stem cells are described. Differences between findings from animal and human models impacting generalizability of research to clinical therapeutics are identified. These differences are important because ethical/political concerns limit research on human embryonic cells in the United States. Cell surface markers that identify pluripotent, multipotent, or specific lineage stem cells and thereby the potential to differentiate into specific tissues (including cardiovascular tissues) are discussed. This review also summarizes the current use of stem cells in the treatment of a range of diseases and the limitations associated with their use.
The second article, "Stem Cell Therapy for Cardiac Repair," describes evidence, primarily from animal models of myocardial ischemia, suggesting that stem cell therapy elicits some improvement in heart function. But the question is "why?"-because few stem cells seem to localize and stay in the damaged tissue, and few of those that do stay demonstrate contractile properties. As a result, several questions remain. Which source of stem cells would be best to use? What would be the best way to deliver them to the heart? How can the cells be convinced to stay? How can they be convinced to differentiate into functional myocardial cells? And, under the circumstances whereby few stem cells differentiate into cardiac muscle cells and remain in the heart, how is functional improvement achieved? The results of current studies that attempt to answer these questions are examined.
Both chemical signal molecules and the surrounding physical environment (eg, physical supporting structures) provide cues that stimulate stem cells to differentiate and functionally integrate into a given tissue. The third article in this series, "Cardiac Tissue Engineering," reviews progress in bioengineering approaches aimed at supplying physical supporting substrate to the heart such that the structure could help contain stem cells and entice them to organize into functional myocardial tissue. Scaffolds may be implanted into the heart and then populated with stem cells. Alternatively, scaffolds may be populated with cells ex vivo and then implanted. In the not-so-distant past, some of these bioengineering methods would have seemed to come from the pages of science fiction. This last article of the series describes early steps in the evolution of tissue engineering from the bench to the bedside.
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