Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling.
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.


RESULTS
Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55+/-5.6% to 30+/-5.4% (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 (31P magnetic resonance spectroscopy; 1.06+/-0.30 in infarcted hearts [n=9] versus 1.90+/-0.15 in normal hearts [n=8; P<0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34+/-0.29; n=7; P<0.05). 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 (19.7+/-9.8%, P<0.01), whereas the left ventricular ejection fraction improved to 42.0+/-6.5% (P<0.05 versus myocardial infarction). Only 0.35+/-0.05% 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, n=6; no cyclosporine A, n=7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and approximately 2%, 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 (P<0.05).


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.
Zeng
Lepeng
L
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minn, USA.
Hu
Qingsong
Q
Wang
Xiaohong
X
Mansoor
Abdul
A
Lee
Joseph
J
Feygin
Julia
J
Zhang
Ge
G
Suntharalingam
Piradeep
P
Boozer
Sherry
S
Mhashilkar
Abner
A
Panetta
Carmelo J
CJ
Swingen
Cory
C
Deans
Robert
R
From
Arthur H L
AH
Bache
Robert J
RJ
Verfaillie
Catherine M
CM
Zhang
Jianyi
J
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D016572:Cyclosporine / Q000627:therapeutic use; D004734:Energy Metabolism; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D023421:Models, Animal; D039902:Multipotent Stem Cells / Q000637:transplantation*; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000737:chemistry; D032383:Myocytes, Cardiac / Q000166:cytology; D018919:Neovascularization, Physiologic; D010725:Phosphocreatine / Q000032:analysis; D011897:Random Allocation; D012038:Regeneration; D034421:Sus scrofa; D013552:Swine; D020257:Ventricular Remodeling
D007166:Immunosuppressive Agents; D010725:Phosphocreatine; D016572:Cyclosporine; D000255:Adenosine Triphosphate