Cardiac progenitor cells (CPCs) possess the IGF-1-IGF-1 receptor system which promotes cell survival, growth and differentiation. Therefore, we tested whether the local injection of CPCs together with the prolonged release of IGF-1 by self-assembling peptides enhanced myocardial regeneration after infarction. The possibility was raised that this strategy may improve cardiac repair by potentiating the regenerative response of the delivered and resident CPCs. Myocardial infarction was induced in rats and after the injection of 100,000 clonogenic immunocompatible EGFP-positive-CPCs in the border zone, biotinylated IGF-1 nanofibers were delivered to the same region. Four groups of animals were used for comparison: infarcted hearts injected with peptide only, infarcted hearts injected with CPCs only, untreated infarcted hearts and sham operated hearts. All animals received BrdU throughout the 1 month experimental period for the recognition of newly formed cells. Infarct size, ~60%, was comparable in the 4 groups. Although all treated-infarcted hearts showed a reduction in chamber volume and an increase in wall-thickness-to-chamber volume ratio and LV mass-to-chamber volume ratio, the combined treatment had the most positive effect. Similarly, LVEDP, LVDP, and dP/dt improved predominantly in infarcted hearts exposed to CPCs and IGF-1 which possessed a larger number of regenerated myocytes. The newly formed BrdU-positive myocytes consisted of EGFP-positive and EGFP-negative cells. The former category corresponded to the progeny of the injected CPCs and the latter was the product of differentiation of resident CPCs. The regenerated myocytes showed a high degree of differentiation; 20% of myocytes had a volume 2,000 –10,000 μm
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. This level of maturation was not observed in infarcted hearts treated only with CPCs or IGF1 releasing peptides. Also, administration of CPCs and IGF-1 led to the formation of numerous resistance arterioles and capillary structures within the regenerated myocardium. Thus, the combination of CPCs and IGF-1 biotinylated nanofibers results in an unprecedented degree of myocardial recovery of structure and function after infarction. Importantly, the regenerated myocytes acquire the differentiated adult phenotype.
Identification and Characterization of a Novel Multipotent Sub-Population of Sca-1+ Cardiac Progenitor Cells for Myocardial Regeneration