The adult bone marrow non-hematopoietic stem cells known as mesenchymal stem cells (MSCs) promote functional cardiac recovery in animals with myocardial infarction (MI). In several countries these cells have been administered to patients with MI with reported beneficial effects. Despite the efficacy of MSC administration, most studies have shown that few of the cells engraft long-term and that only a portion of the surviving cells appear to differentiate to a mature cardiac phenotype. In animals injection of concentrated conditioned medium into cardiac muscle appears to have effects similar to those of direct injection of cells, implying that secreted factors from the cells comprise the principle basis for the benefits. Our preliminary data demonstrate that non-hematopoietic human bone marrow stem cells can exert cardiac protective and reparative effects when delivered intravenously (IV) to animals with MI. Furthermore, we show that serum-free medium conditioned by mixed MSCs or by standardized MSCs isolated by magnetic sorting for the p75 low affinity nerve growth factor receptor (p75LNGFR;p75MSCs) can support the growth and survival of adult cardiac stem/progenitor cells through activation of the transcription factor STAT3. Because MSCs are prepared from a heterogeneous mixture of adherent cells, it is desirable to have a standardized isolation procedure for a population of progenitor cells that predictively imparts cardiac protection and/or repair. We have recently isolated sub-populations of non-hematopoietic stem cells from the total mononuclear cells of bone marrow by specific cell surface epitopes. They may be particularly well-suited for cardiac preservation based on their expression profiles of secreted proteins. Comparing the effectiveness of one of these sub-populations (p75MSCs) to mixed adherent MSCs, we will determine whether intravenous or intramuscular administration of non-autologous stem cells can be used to provide paracrine-based cardiac cell therapy. We will identify the factors secreted by the stem cells that are effective and determine whether the mechanism of action is sparing of existing cardiomyocytes by inhibition of apoptosis or necrosis or augmenting the proliferation and survival of endogenous cardiac stem cells.
SPECIFIC AIMS 1. To identify a cardioprotective sub-population of human bone marrow stem cells and determine the growth conditions and timing of administration necessary to rescue cardiac function after MI in immunodeficient mice. 2. To determine the ability of strain-mismatched murine bone marrow stem cells delivered intravenously or intramuscularly to promote cardiac protection or recovery after MI in immunocompetent mice. 3. To identify the specific factors secreted by the stem cells that preserve cardiac function.
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