Recent reports have raised the possibility that use of adult stem cells from bone marrow may provide dramatic new therapies for both acute and chronic cardiac diseases. However, to develop a safe and effective therapy with adult stem cells, a number of problems and issues must be resolved. We will focus our attention on the adult stem cells from bone marrow referred to as either mesenchymal stem cells or marrow stromal cells (MSCs). The cells have several advantages over other stem cells in that they can readily be isolated from a patient to be treated, they are not tumorogenic, they are multipotential for differentiation into many cell phenotypes, and they have shown a remarkable ability to home to sites of tissue injury and repair the injury. We will first thoroughly characterize distinct subclasses of MSCs that we have recently identified and that apparently include the earliest progenitors and the most multipotential cells in standard cultures of MSCs. We will then compare standardized preparations of the cells for engraftment and differentiation first in a simple ex vivo co-culture system with cardiac cells, and then in rat in vivo models for acute and chronic ischemic damage to heart.
The Specific Aims are: (1) Further characterize the special subclass of stem-like cells that we have recently isolated from cultures of MSCs and that have unusually long telomeres and propagate more rapidly than parallel samples of MSCs. We will test the hypothesis that the cells are pre-RS cells, i.e. precursors of the rapidly self-renewing cells (RS cells) that we previously identified as a sub-population of early progenitors in standard cultures of MSCs. (2) Use an ex vivo co-culture system to compare the ability of the putative pre-RS cells, RS cells, mMSCs, and marrow mononuclear cells, to repair hypoxic damage to cardiac cells either through direct differentiation of the cells or through cell fusion. (3) Isolate and characterize putative pre-RS ceils, RS cells, mMSCs, and mononuclear cells from rat bone marrow for testing in in vivo models of cardiac ischemia in Specific Aim 4. (4) Determine the ability of rMSCs, mMSCs, pre-RS, RS, and unfractionated mononuclear cells from rat marrow to engraft into and produce functional improvement and reduce damage in rat models of acute myocardial infarction (ischemia-reperfusion) and coronary arteriogenesis (intermittent repetitive ischemia).
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