Abstract
AimsEndogenous cardiac progenitor cells, expanded from explants via cardiosphere formation, present a promising cell source to prevent heart failure following myocardial infarction. Here we used cine-magnetic resonance imaging (MRI) to track administered cardiosphere-derived cells (CDCs) and to measure changes in cardiac function over four months in the infarcted rat heart.Methods and ResultsCDCs, cultured from neonatal rat heart, comprised a heterogeneous population including cells expressing the mesenchymal markers CD90 and CD105, the stem cell marker c-kit and the pluripotency markers Sox2, Oct3/4 and Klf-4. CDCs (2×106) expressing green fluorescent protein (GFP+) were labelled with fluorescent micron-sized particles of iron oxide (MPIO). Labelled cells were administered to the infarcted rat hearts (n = 7) by intramyocardial injection immediately following reperfusion, then by systemic infusion (4×106) 2 days later. A control group (n = 7) was administered cell medium. MR hypointensities caused by the MPIOs were detected at all times and GFP+ cells containing MPIO particles were identified in tissue slices at 16 weeks. At two days after infarction, cardiac function was similar between groups. By 6 weeks, ejection fractions in control hearts had significantly decreased (47±2%), but this was not evident in CDC-treated hearts (56±3%). The significantly higher ejection fractions in the CDC-treated group were maintained for a further 10 weeks. In addition, CDC-treated rat hearts had significantly increased capillary density in the peri-infarct region and lower infarct sizes. MPIO-labelled cells also expressed cardiac troponin I, von Willebrand factor and smooth muscle actin, suggesting their differentiation along the cardiomyocyte lineage and the formation of new blood vessels.ConclusionsCDCs were retained in the infarcted rat heart for 16 weeks and improved cardiac function.
Highlights
The optimum stem cell for treatment of the infarcted heart has yet to be established
cardiosphere-derived cells (CDCs) were retained in the infarcted rat heart for 16 weeks and improved cardiac function
Use of a cardiac progenitor cell, a model of infarction/reperfusion and high resolution non-invasive magnetic resonance imaging (MRI), has allowed us to further validate the potential of CDCs by showing that CDCs are retained in the heart for at least 16 weeks and we show for the first time that CDC therapy provides long-term improvement in cardiac function
Summary
The optimum stem cell for treatment of the infarcted heart has yet to be established. Despite promising studies using bone marrow cells in animal models, the results from the clinical trials have not been conclusive [1], causing a shift in interest to endogenous cardiac stem cells, which were first identified in 2003 [2,3]. Further expansion of cardiosphere-derived cells (CDCs) as an adherent monolayer [5] generated a mixed population, comprising c-kit+ cardiac progenitor cells and CD90+ cardiac mesenchymal cells, and provided a sufficient number of cells for therapy within 1–2 months. Improved ejection fraction has been reported in the infarcted rat heart at 6 weeks after administration of CDCs or EDCs [12]. As with other stem cell types [13], the observed improvement in cardiac function with stem cell therapy utilising cardiac-derived cells has been ascribed both to differentiation of donor cells, providing new myocytes and blood vessels, and to the release of paracrine factors, improving cardiomyocyte survival, activating endogenous cardiac stem cells and angiogenesis [11]
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