Abstract 3904: Transplantation of Human Unrestricted Somatic Stem Cells from Cord Blood Repairs Myocardial Infarction through Pleiotropic Mechanisms of Cardiac Myoangiogenesis
Recently, CD34−/CD45− unrestricted somatic stem cells (USSCs) were identified from human cord blood. However, therapeutic potential of USSCs for cardiac repair and its mechanism still warrants further investigation. PBS, 1x106 human fibroblasts (Fb), 1x105 USSCs (LD) or 1x106 USSCs (HD) were intramyocardially administered after ligating LAD of nude rats (n=10 in each group). Echocardiography and a micro-tip conductance catheter revealed a dose-dependent improvement of LV function 28 days after USSC transplantation (EF: HD, 67.9±2.8; LD, 55.1±2.8; Fb, 44.0±2.0; PBS, 38.7±2.4%; P<0.01). Necropsy examination indicated a dose-dependent inhibition of LV fibrosis at day 28 (HD, 14.8±1.0; LD, 19.6 ±0.8; Fb, 33.2±1.4; PBS, 31.5±1.2%.; P<0.01). Double staining for GATA4 and human mitochondria antigen (HMA) or that for Nkx2.5 and HMA disclosed the development of cardiogenic progenitor cells derived from USSCs but not fibroblasts at day 5. Dual staining for cardiac troponin-I (cTn-I) and human nuclear antigen (HNA) or that for von Willebrand factor and HNA demonstrated a dose-dependent development of human cardiomyocytes (hCMCs) and endothelial cells (hECs) at day 28 (hCMC; HD, 239.5±15.9; LD, 56.5±4.34; Fb, 0±0; PBS, 0±0 /mm2; P<0.01) (hEC; HD, 79.3±3.2; LD, 52.8±3.1; Fb, 10.1±2.5; PBS, 0±0 /mm2; P<0.01). Real-time PCR at day 5 revealed the enhanced expression of human-specific cardiogenic (BNP, cTn-I, MHC-βand Nkx 2.5) and angiogenic (VEGF, bFGF, HGF and SDF-1) markers in USSC groups than control groups, supporting autocrine effects of USSCs for the cardiac repair. On the other hand, double staining for Ki67 and cTn-I disclosed a dose-dependent increase in proliferating CMCs at day 7 (HD, 361.5±26.2; LD, 224.6±14.3; Fb, 41.8±16.6; PBS, 3.8±0.7 /mm2, P<0.01), suggesting the paracrine effect of USSCs on the resident CMCs. FISH analysis for human and rat genomes revealed very few incidence of cell fusion (cell fusion ratio: 1.53±0.82%) between transplanted USSCs and recipient cells. USSCs may have significant and dose-dependent potential for cardiac myoangiogenesis through autocrine and paracrine mechanisms, resulting in functional and histological recovery from myocardial infarction.