Abstract
IntroductionA number of questions remain unanswered in the field of cell therapy for acute myocardial infarction, including what is the optimal cell type, and can therapeutic efficacy be enhanced by conditioning regimens. In this study, we sought to address these questions by directly comparing the effect of bone marrow-derived mesenchymal stem cells and unrestricted somatic stem cells delivered 24 hours post-myocardial infarction and by determining if the therapeutic efficacy of unrestricted somatic stem cells could be enhanced by exposing the cells to guiding factors before cell transplantation.MethodsUnrestricted somatic stem cells were guided by exposure to 50 ng/mL basic fibroblast growth factor, 20 ng/mL hepatocyte growth factor and 20 ng/mL bone morphogenetic protein-2 for 24 hours. Using a Sprague-Dawley rat model of acute myocardial infarction, we transplanted cells by intramyocardial injection 24 hours post-myocardial infarction. Cardiac function was serially measured using echocardiography, and histological analyses of infarct morphology, angiogenesis and apoptosis were obtained. Transcriptomic and proteomic changes were assessed using microarray and real-time quantitative PCR.ResultsWhen assessed 28 days after the myocardial infarction, the delivery of mesenchymal stem cells 24 hours post-myocardial infarction did not improve ejection fraction (P = 0.19), and did not prevent the decline in ejection fraction observed in the absence of cell therapy (P = 0.17). The administration of unrestricted somatic stem cells also did not improve ejection fraction (P = 0.11), but did prevent a further decline in ejection fraction (P = 0.001). Delivery of guided unrestricted somatic stem cells significantly improved ejection fraction (P = 0.03). Guided unrestricted somatic stem cells restored function to a greater extent than mesenchymal stem cells (P = 0.03). The infarct area (P = 0.2), apoptosis (P = 0.07) and angiogenesis (P = 0.09) did not differ between groups. Microarray analysis revealed that, following pre-implantation guiding, the gene groupings of mitosis, signalling and angiogenesis were highly overrepresented, mediators of apoptosis were overrepresented, and cardiomyocyte-associated genes were not differentially expressed.ConclusionsThese results suggest that guided unrestricted somatic stem cells have a moderate capacity to repair cardiac damage and that they are more effective than mesenchymal stem cells in restoring cardiac function after a myocardial infarction. The mechanism of the benefit was not fully elucidated in this study, but these observations may be mediated by favorable dysregulation of angiogenic and apoptotic gene groupings.
Highlights
A number of questions remain unanswered in the field of cell therapy for acute myocardial infarction, including what is the optimal cell type, and can therapeutic efficacy be enhanced by conditioning regimens
There was no difference between groups in the Ejection fraction (EF) measured at this time-point, but the mesenchymal stem cells (MSC) group did have a trend towards a higher EF than the other groups
MSC administration resulted in an EF at sacrifice of 55.3% (SE: 3.9%; n = 6), which was not statistically significantly higher than the EF observed in the myocardial infarction (MI) only (n = 5) group (39.7%; standard error (SE): 4.3%; P = 0.17), or the Media (n = 6) group (41.2%; SE: 3.9%; P = 0.24) at the same time-point (Figure 1a)
Summary
A number of questions remain unanswered in the field of cell therapy for acute myocardial infarction, including what is the optimal cell type, and can therapeutic efficacy be enhanced by conditioning regimens. The ability of transplanted cells to engraft and transdifferentiate has been shown by a number of investigators [5,6,7], but the extent of engraftment is low, and probably cannot account for the magnitude of effect, suggesting that alternative mechanisms play at least as important a role. One such complementary mechanism is the paracrine effect, in that mesenchymal stem cells (MSC) may mediate the functional improvement through secretion of soluble cytokines and growth factors [8]. The exposure of MSC to a ‘cardiopoietic cocktail’ was shown to enhance the reparative capacity of MSC by promoting their differentiation into a cardiac progenitor [10]
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