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.

Fig. 1.

Study design. n, No. of pigs.

Fig. 2.

Long-term improvement in ventricular function after multipotent progenitor cell (MPC) transplantation. A: MPC transplantation leads to an improvement in ejection fraction as early as 10 days after cell transplantation that persists up to 4 mo (P < 0.05). ▲, Control; ■, cell treated. B: tabulated form of the ejection fraction data from 10-day, and 1-, 2-, 3-, and 4-mo MRI. Values are means ± SD; n, no. of pigs. *P < 0.05 vs. control.

Fig. 3.

Long-term reduction in scar size after MPC transplantation. Solid bars, myocardial infarction; open bars, myocardial infarction + cell. LV, left ventricular. Values are means ± SD.

Fig. 4.

Heat map showing all differentially expressed transcripts found using Affymetrix array analyses of heart tissue, with and without exposure to stem cells. Expression levels are normalized to the average value of the untreated heart tissue and are log transformed. The names associated with each probe are the human names obtained from the annotation described in the materials and methods section. The probe names can be found in Table 5. Normalized and raw data are available at GEO under the entry GSE14643 (http://www.ncbi.nlm.nih.gov/geo/).