Abstract 3824: Local Activation or Implantation of Cardiac Progenitor Cells Rescues Scarred Infarcted Myocardium Improving Cardiac Function
The goal of this study was to test whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by HGF and IGF-1 (GFs) invade the scar and generate new myocardium improving cardiac function. Myocardial infarction was produced in rats and 20 days later animals were injected with EGFP-tagged clonogenic CPCs, GFs or vehicle. The ability of CPCs to enter the scar was evaluated ex vivo by two-photon microscopy shortly after treatment. Single CPCs were detected at 4 hours and clusters of moving cells were present at 24 hours within tunnels of collagen. Injected and GF-activated CPCs migrated with a different pattern. EGFP-positive-CPCs moved at a speed of 14 μm/h and there were ~500 cells/mm3 of scar; GF-activated CPCs moved at higher speed (30 μm/h) but there were only ~270 cells/mm3 of scar. To evaluate the effects of CPC delivery and GF administration on cardiac regeneration, rats were sacrificed 20 days after therapy. With both treatments, the infarcted region showed a 2-fold thicker wall and regeneration resulted in a 40% recovery of the scar with increased ejection fraction. New myocytes formed gap and adherens junctions with preexisting cells. Regeneration was confirmed by FACS analysis of cells enzymatically dissociated from the scarred region of treated and untreated-hearts. EGFP-positive myocytes and BrdU-positive myocytes obtained from infarcted hearts injected respectively with CPCs and GFs constituted ~26% of the cell pool. In untreated-infarcts, BrdU-positive myocytes were 1% of the cell population. New myocytes contracted in response to electrical stimulation and exhibited higher cell shortening than resident cells. The comparable effects on myocardial regeneration obtained by CPC delivery and GF-activation of resident CPCs may be explained by the pattern of CPC migration in the scar; the higher number of cells found with CPC injection was compensated by the faster speed of GF-activated CPCs leading to a comparable degree of CPC accumulation in the scar. Thus, CPCs locally activated by GFs or injected in the border zone can rescue a large portion of the scar protecting the infarcted heart from the progressive increase in cavitary dilation, decrease in wall thickness and deterioration in function.