Published Online
on March 26, 2007

A more recent version of this article appeared on April 10, 2007

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Submitted on August 31, 2006
Accepted on February 9, 2007

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

Lepeng Zeng PhD, Qingsong Hu MD, MS, Xiaohong Wang MD, PhD, Abdul Mansoor MD, PhD, Joseph Lee PhD, Julia Feygin BS, Ge Zhang MD, PhD, Piradeep Suntharalingam BS, Sherry Boozer BS, Abner Mhashilkar PhD, Carmelo J. Panetta MD, Cory Swingen PhD, Robert Deans PhD, Arthur H.L. From MD, Robert J. Bache MD, Catherine M. Verfaillie MD, and Jianyi Zhang MD, PhD^*

From the Department of Medicine (L.Z., Q.H., X.W., A. Mansoor, J.L., J.F., G.Z., C.J.P., C.S., A.H.L.F., R.J.B., J.Z.) and Stem Cell Institute (L.Z., C.M.V.), University of Minnesota Medical School, Minneapolis, Minn; and Athersys, Inc (P.S., S.B., A. Mhashilkar, R.D.), Cleveland, Ohio.

^* To whom correspondence should be addressed. E-mail: zhang047{at}umn.edu.

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 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 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.

Key words: cells • heart failure • hypertrophy • magnetic resonance imaging • metabolism • myocardial contraction • myocardial infarction

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