Abstract 19220: Potential of Human Cardiac Progenitor Cells from Young versus Old Donor Hearts in Cardiac Protection against Ischemic Left Ventricular Dysfunction and Late Remodeling

Abstract

Introduction: Recent discovery of c-Kit + resident cardiac progenitor cells (CPC) has demonstrated cardiac regenerative capacity, which is lost upon increasing age in mice. Accordingly, we hypothesized that c-KIT + -selected CPC from young human hearts (yCPC) have a greater myocardial repair potential after myocardial infarction (MI) than CPC from old patients (oCPC). Methods: After Ethics Committee approval, cardiac biopsies from young (1-15y old) and old (58-80y old) patients, undergoing corrective or valve surgery were obtained. After collagenase-based digestion, cells were culture-expanded for 2 passages prior to c-KIT + selection using magnetic beads. Purity was confirmed using qRT-PCR for c-KIT, GATA4, CD90, CD105, DDR2, CD31 and MYH11 expression levels. To trace transplanted cells, CPC were lentivirally tagged with GFP. After permanent LAD coronary artery ligation in immunodeficient mice, 250,000 CPCs were injected in the infarct border zone (4x 62,500 cells/2.5 μl; yCPC, n =8; oCPC, n =6; or PBS, n =6). Cardiac ultrasound (VisualSonics, 3D 30 MHz probe) was performed at baseline, 1 and 35 days after MI. At 35 days post-MI, infarct remodeling and cell survival was evaluated using Sirius red and CPC engraftment by anti-GFP staining. Results: In contrast to low MYH11 and CD31 expression levels, c-KIT and GATA4 were markedly and equally expressed in yCPC and oCPC, whereas transcript levels of DDR2, CD105 and CD90 were 89, 109 and 56% higher in oCPC compared to yCPC. Systolic function was better preserved in yCPC than in oCPC and PBS-treated mice 24h after MI (LVEF from baseline - D1: 53±1 - 38±3 vs. 52±3 - 30±5 vs. 50±3 - 27±4%; ESVi from baseline - D1: 3.7±0.2 - 5.1±0.4 vs. 3.8±0.5 - 6.2±0.7 vs. 3.9±0.5 - 6.5±0.6ml/mm 2 ). Moreover, after 35 days, the dilatory response was reduced in yCPC compared to oCPC and PBS-treated mice (EDVi from D1 - D35: 8.3±0.5 - 13.5±1.3 vs. 8.8±0.5 - 16.7±1.8 vs. 8.5±0.5 - 16.6±1.3ml/mm 2 ). Improved remodeling was consistent with a markedly greater rim of surviving myocardium while anti-GFP staining showed only rarely retained CPC. Conclusions: In summary, these findings suggest enhanced protection by c-KIT + CPC isolated from young donor hearts against acute systolic left ventricular dysfunction and late remodeling after MI.