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CLINICAL RESEARCH: MOLECULAR AND STEM CELL IMAGING

Multimodality Noninvasive Imaging Demonstrates In Vivo Cardiac Regeneration After Mesenchymal Stem Cell Therapy

Luciano C. Amado, MD^_*,, Karl H. Schuleri, MD^_*,, Anastasios P. Saliaris, MD^_*,, Andrew J. Boyle, MBBS, PhD^_*,, Robert Helm, MD^_*, Behzad Oskouei, MD^_*,, Marco Centola, MD^_*,, Virginia Eneboe, VT^_*,, Randell Young, MVD, Joao A.C. Lima, MD^_*, Albert C. Lardo, PhD^_*, Alan W. Heldman, MD^_*, and Joshua M. Hare, MD^_*,,1,_*

^_* Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Institute for Cell Engineering (ICE), Johns Hopkins University School of Medicine, Baltimore, Maryland
OsirisTherapeutics, Baltimore, Maryland

Manuscript received February 27, 2006; revised manuscript received June 6, 2006, accepted June 29, 2006.

^_* Reprint requests and correspondence: Dr. Joshua M. Hare, Johns Hopkins Medical Institutions and Institute for Cell Engineering (ICE), Division of Cardiology, BRB 651, 733 North Broadway, Baltimore, Maryland, 21205. (Email: jhare{at}med.miami.edu).

OBJECTIVES: The purpose of this study was to test the hypothesis, with noninvasive multimodality imaging, that allogeneic mesenchymal stem cells (MSCs) produce and/or stimulate active cardiac regeneration in vivo after myocardial infarction (MI).

BACKGROUND: Although intramyocardial injection of allogeneic MSCs improves global cardiac function after MI, the mechanism(s) underlying this phenomenon are incompletely understood.

METHODS: We employed magnetic resonance imaging (MRI) and multi-detector computed tomography (MDCT) imaging in MSC-treated pigs (n = 10) and control subjects (n = 12) serially for a 2-month period after anterior MI. A sub-endocardial rim of tissue, demonstrated with MDCT, was assessed for regional contraction with MRI tagging. Rim thickness was also measured on gross pathological specimens, to confirm the findings of the MDCT imaging, and the size of cardiomyocytes was measured in the sub-endocardial rim and the non-infarct zone.

RESULTS: Multi-detector computed tomography demonstrated increasing thickness of sub-endocardial viable myocardium in the infarct zone in MSC-treated animals (1.0 ± 0.2 mm to 2.0 ± 0.3 mm, 1 and 8 weeks after MI, respectively, p = 0.028, n = 4) and a corresponding reduction in infarct scar (5.1 ± 0.5 mm to 3.6 ± 0.2 mm, p = 0.044). No changes occurred in control subjects (n = 4). Tagging MRI demonstrated time-dependent recovery of active contractility paralleling new tissue appearance. This rim was composed of morphologically normal cardiomyocytes, which were smaller in MSC-treated versus control subjects (11.6 ± 0.2 µm vs. 12.6 ± 0.2 µm, p < 0.05).

CONCLUSIONS: With serially obtained MRI and MDCT, we demonstrate in vivo reappearance of myocardial tissue in the MI zone accompanied by time-dependent restoration of contractile function. These data are consistent with a regenerative process, highlight the value of noninvasive multimodality imaging to assess the structural and functional basis for myocardial regenerative strategies, and have potential clinical applications.

Abbreviations and Acronyms   Ecc = systolic circumferential strain   FOV = field of view   LV = left ventricle/ventricular   MDCT = multi-detector computed tomography   MI = myocardial infarction   MMP = matrix metalloproteinase   MRI = magnetic resonance imaging   MSC = mesenchymal stem cell   TIMP = tissue inhibitor of matrix metalloproteinase

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