Bioenergetic and Functional Consequences of Bone Marrow–Derived Multipotent Progenitor Cell Transplantation in Hearts With Postinfarction Left Ventricular Remodeling

Abstract

Background-The present study examined whether transplantation of adherent bone marrow-derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. Methods and Results-Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55Ϯ5.6% to 30Ϯ5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP ( 31 P magnetic resonance spectroscopy; 1.06Ϯ0.30 in infarcted hearts [nϭ9] versus 1.90Ϯ0.15 in normal hearts [nϭ8; PϽ0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34Ϯ0.29; nϭ7; PϽ0.05). The BZ protein expression of creatine kinase-mt and creatine kinase-m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7Ϯ9.8%, PϽ0.01), whereas the left ventricular ejection fraction improved to 42.0Ϯ6.5% (PϽ0.05 versus myocardial infarction). Only 0.35Ϯ0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, nϭ6; no cyclosporine A, nϭ7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and Ϸ2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (PϽ0.05). Conclusions-Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.

Adhesion Proteins, Stem Cells, and Arrhythmogenesis

“…Similarly, ischemic limb studies have also detected enhanced angiogenic factor expression at the site of injury following MSC injection [38]. The increase in capillary density one month after MSC injection into infarcted hearts has also been shown [37,40,42]. The fact that these improvements persist while only a negligible amount of MSC remains in the myocardium, can also be used to support neovascularization as a main beneficiary mechanism.…”

“…Second, many argue that it is an increase in tissue revascularization [36][37][38][39]. Clusters of MSC have been shown to express key vessel markers, such as von Wille-brand factor, while cardiac markers were absent [36].…”

Fibrin patch-based insulin-like growth factor-1 gene-modified stem cell transplantation repairs ischemic myocardium

“…12 Briefly, animals were anesthetized with 2% inhaled isoflurane and positioned in a supine position within the scanner.…”

Myocardial Layer-Specific Effect of Myoblast Cell-Sheet Implantation Evaluated by Tissue Strain Imaging

“…Myocardial injury and stunning therefore usually originate in the endocardium and, with time, progress to include the epicardium. 26 In general, VEGF expression is activated under hypoxic conditions, a reasonable mechanism for holding oxygen tension constant. 27 Some previous investigators suggested that a soluble VEGF receptor (ie, sVEGFR1) increases in response to hypoxia.…”