Abstract 5374: Increased Levels Of Ciliary Neurotrophic Factor Associated with Long Term Functional Improvement After Bone Marrow Derived Multipotent Progenitor Cell Transplantation in a Porcine Model of Postinfarction Left Ventricular Remodeling
This study examined the mechanisms underlying the long term functional outcome after bone marrow derived multipotent progenitor cell (MPC) transplantation in a porcine model of postinfarction Left Ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the distal left anterior descending coronary artery (LAD). Intramyocardial injection of 50 million lacZ labeled MPC was performed in the periscar region (Cell, n=7) with 5 equal injections immediately after MI, while in control animals (CONT, n=7) saline was injected. Outcome was assessed with MRI and P-31 MRS. Engraftment was studied on histology and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups at 4 months. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (32.2±9.5 vs. 43.4±5.1 in CONT and Cell respectively, p <0.05). This improvement was seen each month and persisted up to 4 months (35.7±6.2 vs. 51.2±4.8 in CONT and Cell respectively, p<0.005). PCr/ATP ratio improved with MPC transplantation (1.88v0.11 vs. 2.13±0.23 in CONT and Cell respectively, p<0.05). Under increased workload with inotropic stimulation, the bioenergetic differences were even more pronounced. There was no significant difference in scar size (scar/LV area*100) at 10 days post infarction (9.7±3.3 vs. 8.3±2.6 in CONT and Cell respectively, p=0.39). However, at 4 months there was a significant decrease in scar size in the MPC treated animals (8.6±3.4 vs. 4.6±1.1 in CONT and Cell respectively, p <0.05). No significant engraftment of MPC was observed on histology at 4 months. Gene chip array analysis identified several genes which were differentially expressed in the two groups. The levels of ZFP91 (Zinc finger protein 91) were increased by 3.73 folds (p=0.003) in the MPC treated group and CNTF (ciliary neurotrophic factor) is co-transcribed with ZFP91. CNTF is known to be involved in decreasing apoptosis and cell death and increasing survival. Thus, MPC transplantation results in long term improvement in ventricular function and myocardial energetics that is associated with a decreased scar size and increased levels of CNTF.
This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).