title: Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction.
abstract: The study examined the long-term outcome of cardiac stem cell transplantation in hearts with postinfarction left ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the left anterior descending coronary artery in miniature swine. Intramyocardial injections of 50 million LacZ-labeled bone marrow-derived multipotent progenitor cells (MPC) were performed in the periscar region (Cell, n = 7) immediately after MI, whereas, in control animals (Cont, n = 7), saline was injected. Functional outcome was assessed monthly for 4 mo with MRI and (31)P-magnetic resonance spectroscopy. Engraftment was studied on histology, and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (Cell, 43.4 +/- 5.1% vs. Cont, 32.2 +/- 5.5%; P < 0.05). This improvement was seen each month and persisted to 4 mo (Cell, 51.2 +/- 4.8% vs. Cont, 35.7 +/- 5.0%; P < 0.05). PCr-to-ATP ratio (PCr/ATP) improved with MPC transplantation, which was most pronounced at high cardiac work states (subendocardial PCr/ATP was 1.70 +/- 0.10 vs. 1.34 +/- 0.14, P < 0.05). There was no significant difference in scar size (scar/LV area * 100) at 10 days postinfarction. However, at 4 mo, there was a significant decrease in scar size in the Cell group (Cell, 4.6 +/- 1.0% vs. Cont, 8.6 +/- 2.4%; P < 0.05). No significant engraftment of MPC was observed. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes and increased levels of myocyte enhancer factor 2a and zinc finger protein 91. In conclusion, MPC transplantation leads to long-term functional and bioenergetic improvement in a porcine model of postinfarction LV remodeling, despite no significant engraftment of stem cells in the heart. MPC transplantation reduces regional wall stresses and infarct size and mitigates the adverse effects of LV remodeling, as seen by a reduction in LV hypertrophy and LV dilatation, and is associated with differential expression of genes relating to metabolism and apoptosis.
authors.affiliation: University of Minnesota Health Science Center, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Mohammad Nurulqadr
authors.initials: MN
authors.lastname: Jameel
authors.forename: Qinglu
authors.initials: Q
authors.lastname: Li
authors.forename: Abdul
authors.initials: A
authors.lastname: Mansoor
authors.forename: Xiong
authors.initials: X
authors.lastname: Qiang
authors.forename: Aaron
authors.initials: A
authors.lastname: Sarver
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Cory
authors.initials: C
authors.lastname: Swingen
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001710:Biotin / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000502:physiology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004734:Energy Metabolism / Q000502:physiology; D015870:Gene Expression / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D039902:Multipotent Stem Cells / Q000637:transplantation*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010725:Phosphocreatine / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D013318:Stroke Volume / Q000502:physiology; D013552:Swine; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D018076:DNA, Complementary; D010725:Phosphocreatine; D012313:RNA; D001710:Biotin; D000255:Adenosine Triphosphate