Determining the effect of aging on bone-marrow derived mesenchymal stem cell cardiac and angiogenic plasticity potential

Coronary vascular disease is the leading cause of death in the United States. After acute myocardial infarction, irreversible loss of cardiac tissue causes contractile dysfunction and eventually leads to congestive heart failure. Reduction of cardiac myocyte loss and repair of the vasculature are important therapeutic goals because the potential for intrinsic repair is limited. Preclinical and limited clinical data support the possibility that bone marrow-derived mesenchymal stem cells may be a suitable cell type to regenerate and repair the heart after infarction. Autologous therapy will depend on the condition of the MSC population, therefore successful and optimal clinical application of cell therapy requires further in depth understanding of the biological properties of cells. The goal of this research was to determine the effectiveness of using MSCs from aged mice in cellular therapy for the treatment of AMI. The central hypothesis for this research was that therapeutic potential of mesenchymal stem cells decreases with age.;This research utilized global gene expression analysis to investigate molecular differences in MSCs harvested from three different age groups of mice. These experiments first describe the isolation and characterization of BM-derived MSCs from 2m, 8m, and 26m. The three age groups were chosen to represent a young and healthy, adult, and elderly phenotype respectively. Once the cells were confirmed to be bone-marrow derived MSCs, microarray analysis was performed to investigate changes in gene expression with respect to aging. Furthermore, both in vitro and in vivo experiments were completed to analyze the functional and molecular characteristics of the MSCs. The data identified age-related defects in mouse MSCs as well as determined the molecular basis for these deficiencies.;This study indicates that MSCs from 26m mice are severely deficient in the induction of angiogenesis and cardiac repair due to defective paracrine factor secretion caused by decreased expression of growth factor/cytokine genes. Hypoxia attenuates the deficiency in the aged mice, whereas in young mice low oxygen promotes secretion of paracrine growth factors. It was determined a dysfunction in HIF-1alpha signaling was present in MSCs from 26m mice and is regulated by the PI3K/Akt signaling in MSCs. During aging, this pathway is not activated during exposure to hypoxia that culminates in a failure of MSCs from old mice to secrete bioactive levels of VEGF.;Furthermore, two novel and important and novel aspects of this study were the discovery that cell cycle regulation gene expression decreases with age and MSCs have increased insulin resistance with age. Increased insulin resistance in this cell type with aging is likely to have profound effects on the clinical outcomes of using these cells therapeutically. Likewise, loss of cell cycle regulation during proliferation could also lead to undesirable clinical effects. This research addresses what effects aging has on these MSCs and identified important differences in the cells from old and young mice. This research lays a foundation for future experiments to test the value of aged stem cells as a treatment for cardiac disease. Gaining insight to the repair potential of these cells with respect to age will help to better define future trials of autologous stem cells not only for heart disease but for all of the many applications proposed for these cells.