Abstract 1891: Human Vascular Progenitor Cells Form Conductive Coronary Artery in Dogs with Critical Coronary Artery Stenosis

Abstract

To determine whether the human heart possesses a coronary vascular progenitor cell (VPC) that regulates the growth of endothelial cells (ECs), smooth muscle cells (SMCs), and vasculogenesis, we have identified vascular niches composed of c-kit-positive KDR-positive VPCs within the coronary circulation. VPCs are connected by functional gap junctions to ECs, SMCs and fibroblasts which operate as supporting cells. Isolated VPCs were self-renewing and clonogenic and differentiated into ECs and SMCs. Subsequently, we tested whether human VPCs possess the ability to create conductive coronary arteries in immunosuppressed dogs with critical coronary stenosis. The presence of a critical stenosis was documented by the absence of reactive hyperemia after the release of a 15 sec occlusion of the LAD. VPCs infected with a lentiviral vector carrying EGFP were then injected above, laterally and below the site of constriction. At 10 days, the lack of reactive hyperemia persisted while at 30 days there was a slow return of CBF possibly mediated by the formation of coronary vessels. Thus, myocardial perfusion was determined; gold-labeled microspheres were injected with the LAD open to establish baseline CBF while lutetium-labeled microspheres were administered after LAD occlusion. Multiple sections from the region proximal to the region distal to the occlusion were processed to evaluate CBF distribution. Every other section was collected for histology. CBF at baseline was similar in all sections but after LAD occlusion there was a doubling in CBF in the fully dilated coronary circulation distal to the stenotic vessel. Histologically, new coronary arteries, 0.8–1.5 mm in diameter, were detected in proximity of the stenotic vessel together with resistance arterioles and capillaries, pointing to vessel regeneration as the mechanism of enhanced CBF in the ischemic myocardium. ECs and SMCs within the vessel wall were all EGFP-positive; the human origin of these cells was confirmed by the detection of human DNA sequences with an Alu probe. In conclusion, the human heart possesses a coronary VPC that can be isolated and expanded in vitro for subsequent autologous transplantation in patients with coronary artery disease and the formation of a biological bypass.