Presented to the AACT 2015 Conference
Cardiovascular disease remains the number one cause of death in the world, but it is also the leading cause of disability, reduced functional capacity, as well as significant economic impact. This realization has led the World Health Organization to make chronic disease its number one priority for the next decade. CVD presents in many different forms and across all ages, from congenital heart disease, to stroke, but the prevalence increases rapidly beyond the age of 50 years. The aging of the population across the globe makes CV disease causes an even greater mandate to find new cost-effective solutions.
The heart has always been thought to be terminally differentiated, and incapable of hyperplasia or meaningful regeneration, but the proof of apoptosis, which entails an annual turnover of 3-5% of all cells, including the heart, requires the capability of the heart to regenerate. However, inducing meaningful regeneration in the heart by delivery of stem cells has proven to be more challenging than anticipated. Some of the proven unique requirements include not only survival once implanted, but establishing electrical coupling to native cardiomyocytes, and ability to generate new cells.
The most commonly held understanding of the mechanism of action of stem cells is that cells do not remain where they are implanted and become new cardiomyocytes, but as most labeling studies suggest that transplanted stem cells remain for only a matter of days. Their primary role is to activate native regenerative/repair mechanisms. Challenges encountered over the past decade include delivering adequate number of cells, route of delivery, as well as defining the optimal source and type of cells for cardiac repair.
Use of stem cells for CV disease logically began over 10 years ago targeting the leading cause of death in the world, acute myocardial infarction. Similarly, the almost exclusive source of cells was from autologous bone marrow, which was thought to be not only the safest, but naively understood to be the only source of stem cells aside from embryos. The demonstration of pro-angiogenesis and some cardiogenesis in many animal models using bone marrow mononuclear cells made it the logical source. However, the results have been disappointing, using the primary surrogate end point of success of improvement in ejection fraction, which although shown to be statistically significant, by meta-analyses to provide only 2-4% absolute difference from baseline. Several explanations for these results include the documented decline in the number of stem cells in the bone marrow with advancing age, as well as a decline in telomere length and function. Another important part of the approach to AMI therapy was to deliver the cells by direct intracoronary injection, assuming that there would be sufficient expression of inflammatory signals that would cause the cells to home directly to the site of the MI.
The second focus of stem cells for CVD has been heart failure. The initial clinical trials used autologous bone marrow, with similar results, although the cells were delivered directly into the ventricular wall to assure local benefit. However, there has been a significant expansion of the types and sources of stem cells now in clinical trials for heart failure.
Perhaps the most promising advance in stem cell therapy for CVD has been the finding that mesenchymal type stem cells have minimal expression of critical surface markers that define self from foreign cells, thereby inducing almost no alloreactivity with their use, regardless of source, making them immune-privileged and able to be used with an ideal young healthy donor source into patients of any HLA type, age or stage of HF. These cells are now in Phase III clinical trial. Other novel approaches now in clinical trial includes the identification of resident cardiac stem cells, which can be obtained from heart tissue and expanded in culture, and then injected into the heart with not only impressive improvement in ejection fraction, but also the first suggestion of being able to show regression of actual scar by MRI scan. In addition, it has been shown that genetic engineering of cells by addition of as few as four transcription factors, can transform skin fibroblasts into functioning cardiomyocytes. Phase III clinical trials have been completed in Europe with this approach. Finally, there are a number of genes that may be the effectors of stem cells, and are being transfected into stem cells in culture to up-regulate their expression in specific settings such as nitric oxide in acute MI.
Nearly all of these novel approaches to use of stem cells are now being explored in clinical trials in two other major forms of CVD, specifically peripheral vascular disease and stroke, with similar encouraging results.
To cite this article
Stem Cells for Cardiovascular Disease
CellR4 2015; 3 (5): e1634
Published online: 11 Sep 2015