Abstract
Because of the potential of stem cells and stromal cells to differentiate into vascular cells, their most salubrious role in the treatment of patients with ischemic heart disease may be as prophylactic agents preventing infarction by stimulating coronary collateral growth (CCG). Therefore, we determined if multipotent stromal cells (MSCs: CD59+, CD90+) would amplify CCG in a rat model of ischemia, but without infarction. Rats were instrumented with a pneumatic snare around the left anterior descending artery and subjected to repetitive ischemia (RI: 24 40 sec occlusions/day for 10 days) to stimulate CCG. CCG was determined from the ratio of flows (radioactive microspheres) to the collateral-dependent (during LAD occlusion) and normal zones (CZ/NZ, where 1.0, indicates CCG has completely restored flow to the area at risk). After RI, CZ/NZ was 0.33±0.04, which was greater than in shams indicating RI stimulated collateral growth. In rats treated with MSCs (intraventricular injection of 8 x 10 5 at the time of initial surgery), CZ/NZ was 0.51±0.01 (p<0.05 vs RI). Because the RI protocol does not produce severe tissue injury, we reasoned that the multipotent stromal cells might not home properly to the tissue; therefore we determined if amplification of MSCs adhesion would augment CCG. To accomplish this we ascertained that MSCs adhesion to endothelial monolayers in vitro was augmented (~3X) by treatment with EGF, that we found to upregulate adhesion molecule expression. Injection of EGF-treated MSCs increased CZ/NZ to 0.75±0.07 (p<0.05 vs RI and RI+BMSC). Labeling of MSCs with DiI showed that EGF treatment increased the number of labeled cells in the myocardium and vascular tissues. The fraction shortening (FS, echocardiography) was significantly decreased in the RI group 25.4±0.5% vs sham (37.2±0.3%, p<0.05 vs RI). However, injection of EGF-treated MSCs increased FS significantly (33.4±1.3%) vs RI and RI+MSCs (p<0.05), demonstrating that the increase in collateral flow was functionally significant. Thus MSCs may prove to be effective therapies for the stimulation of coronary collateral growth, but appear to be more effective after interventions are employed to increase their adhesion and homing (in vitro EGF treatment) to the jeopardized myocardium.
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