Fetal and neonatal cardiomyocyte transplantation for the treatment of myocardial infarction

In the past few years cardiac cell transplantation has emerged as a novel therapeutic strategy to treat myocardial infarction and heart failure. Several clinical studies are already under-way, and multipotent stem cells show promise to become the favored cell type to replace lost myocardium. Nevertheless, important data providing insight into the basic mechanisms of this technique and supporting the beneficial effects of a cell transfer therapy have already been obtained in studies involving fetal or neonatal cardiomyocytes. In this chapter we summarize the results from investigations on the potential of fetal and neonatal rat cardiomyocytes to survive, to mature and to structurally and functionally replace host myocardium after implantation in infarcted and non-infarcted rat hearts. In initial experiments human and rat fetal cardiomyocytes were injected into infarcted hearts of adult Sprague-Dawley rats. The expression of smooth muscle alpha-actin was followed as a marker of the fetal cell grafts. The cellular grafts survived for at least 60 days. On the other hand, the continuous presence of fetal alpha-actin also demonstrated a lack of complete maturation of these cells. Immunohistochemical analysis with connexin-43 antibody and the presence of surrounding collagen revealed that areas of transplanted cells were isolated from host myocardium. Nevertheless, transplanted fetal cardiomyocytes attenuated the deterioration of cardiac function after myocardial infarction by echocardiographic analysis, albeit they were not able to reverse defective function. One of the factors that likely determines the effective support of cardiac function, win be the survival of transplanted cells. To assess the number of surviving cells, we used the Y chromosomes of male neonatal cardiomyocytes which were transplanted into female adult rats. PCR analysis revealed that the number of surviving cells decreased within 24 hours after transplantation to about 15% of those injected, but was quite stable thereafter for at least 12 weeks. When injected into the infarcts of rat hearts (ligation of left coronary artery), neonatal cardiomyocytes increased the thickness of the infarcts and improved LV ejection fraction as measured by angiography. Echocardiography revealed a trend towards a smaller internal diameter and an increased fractional shortening. The grafted neonatal cells developed organized sarcomeric structures and aligned parallel to the circumference of the LV. However, similar to the observation for fetal cells, the neonatal cells did not achieve the maturity of adult rat cardiomyocytes. In summary, our data demonstrate that fetal and neonatal cardiomyocytes can survive long term after injection into normal or infarcted adult hearts. They undergo a certain degree of maturation over time, but during the observed periods they do not reach the maturation status of adult cells. Fetal and neonatal cells have beneficial effects on cardiac function of hearts after myocardial infarction, however, they do not completely reverse the contractile deficit of these hearts. Nevertheless, the data are encouraging that in the not too distant future cell therapy may be a new hope for patients who suffer from ischemic heart disease.