Abstract 610: The Pig Heart Harbors Cardiac Stem-Progenitor Cells which Respond to Increasing Growth Factor Stimulation Regenerating the Infarcted Myocardium
Recent reports on murine models have raised the possibility of regenerating contractile myocardial tissue by in situ activation and mobilization of cardiac stem/progenitor cell (CSC) by growth factors (GF). Extrapolation of murine results to the human are doubtful because the human requires ~ 5x103 larger regenerated mass. We sought to establish the effects of CSC in situ mobilization by intracoronary injections of IGF-1 and HGF after MI in pigs. To this aim, in 23 female Yorkshire pigs, a 75 min PTCA LAD occlusion was used to induce acute MI. Five hours later, IGF-1 and HGF were administered to 16 instrumented pigs. Total doses of GF ranged from 200 to 800ng/ml. Saline was injected in the other 7 pigs with MI. Three pigs received a second dose of GFs at 14 days. All pigs were sacrificed at 28 days after MI and GF administration. To track myocardial regeneration, BrdU was administered via osmotic pumps. Cardiac function was measured by echocardiography and LV catheterization. Cardiac tissue from sham operated pigs was collected and CSCs extracted for in vitro analyses. These CSCs displayed stem cell properties of clonogenicity, self-renewal and multipotency similar to rodent CSCs. Moreover, they expressed functional IGF-1R and c-met receptors. The GF-treated infarcted heart showed a significant increase in the number of c-kitpos CSCs in the border of the infarct and even higher in the ischemic area. Most of these CSCs were BrdUpos/Ki-67pos. Many c-kitpos cells expressed the transcription factors, MEF-2C, Ets-1 and GATA6 indicative of myocyte, endothelial cell and smooth muscle differentiation, respectively. Interestingly, the infarcted area was substantially replaced by new myocardium in direct correlation to the amount of GF administered. These hearts had a significant and increasing number of small BrdUpos (up to 14±3%) and Ki-67pos (up to 12±2%) myocytes. Moreover, newly formed vascular structures were evident in the infarcted myocardium. Myocardial regeneration was absent in untreated pigs. Importantly, LV function was significantly improved in GF treated, compared to controls. Therefore, it is possible and practical to produce effective myocardial regeneration post-MI in hearts the size of the human’s following intracoronary injection of GFs.