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(Circulation. 2009;120:S220-S229.)
© 2009 American Heart Association, Inc.

Cell Transplantation and Tissue Regeneration

Mesenchymal Cell Transplantation and Myocardial Remodeling After Myocardial Infarction

Jennifer A. Dixon, MD; Robert C. Gorman, MD; Robert E. Stroud, MS; Shenikqua Bouges, BS; Hamamoto Hirotsugu, MD; Joseph H. Gorman, III, MD; Timothy P. Martens, MD; Silviu Itescu, MBBS; Michael D. Schuster, MD; Theodore Plappert, CVT; Martin G. St John-Sutton, MBBS; Francis G. Spinale, MD, PhD

From the Division of Cardiothoracic Surgery, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center (J.A.D., R.E.S., S.B., F.G.S.), Charleston; the Departments of Surgery and Medicine (R.C.G., H.H., J.H.G., T.P., M.G.S.J.-S.), University of Pennsylvania School of Medicine, Philadelphia; and the Department of Surgery (T.P.M., S.I., M.D.S.), Columbia University, New York.

Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Strom Thurmond Research Center, 114 Doughty St, Suite 625, Charleston, SC 29425. E-mail wilburnm{at}musc.edu

Background— Targeted delivery of mesenchymal precursor cells (MPCs) can modify left ventricular (LV) cellular and extracellular remodeling after myocardial infarction (MI). However, whether and to what degree LV remodeling may be affected by MPC injection post-MI, and whether these effects are concentration-dependent, remain unknown.

Methods and Results— Allogeneic MPCs were expanded from sheep bone marrow, and direct intramyocardial injection was performed within the borderzone region 1 hour after MI induction (coronary ligation) in sheep at the following concentrations: 25x10⁶ (25 M, n=7), 75x10⁶ (75 M, n=7), 225x10⁶ (225 M, n=10), 450x10⁶ (450 M, n=8), and MPC free media only (MI Only, n=14). LV end diastolic volume increased in all groups but was attenuated in the 25 and 75 M groups. Collagen content within the borderzone region was increased in the MI Only, 225, and 450 M groups, whereas plasma ICTP, an index of collagen degradation, was highest in the 25 M group. Within the borderzone region matrix metalloproteinases (MMPs) and MMP tissue inhibitors (TIMPs) also changed in a MPC concentration–dependent manner. For example, borderzone levels of MMP-9 were highest in the 25 M group when compared to the MI Only and other MPC treatment group values.

Conclusions— MPC injection altered collagen dynamics, MMP, and TIMP levels in a concentration-dependent manner, and thereby influenced indices of post-MI LV remodeling. However, the greatest effects with respect to post-MI remodeling were identified at lower MPC concentrations, thus suggesting a therapeutic threshold exists for this particular cell therapy.

Key Words: infarct expansion • stem cells • matrix metalloproteinase • tissue inhibitor of matrix metalloproteinase • fibrosis