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J Thorac Cardiovasc Surg 2008;136:1028-1037
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells

Stephen L. Hendry, II, MDa,*, Koen E.A. van der Bogt, MSa,e,*, Ahmad Y. Sheikh, MDa, Takayasu Arai, MDb, Scott J. Dylla, PhDc, Micha Drukker, PhDc, Michael V. McConnell, MDb, Ingo Kutschka, MDa, Grant Hoyt, BSa, Feng Cao, MD, PhDd, Irving L. Weissman, MDc, Andrew J. Connolly, MD, PhDc, Marc P. Pelletier, MDa, Joseph C. Wu, MD, PhDb,d, Robert C. Robbins, MDa, Phillip C. Yang, MDb,*

a Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford University, Stanford, Calif
b Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, Calif
c Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, Calif
d Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, Calif
e Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

Received for publication September 4, 2007; revisions received December 5, 2007; accepted for publication December 18, 2007.

* Address for reprints: Phillip C. Yang, MD, Department of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94305. (Email: pyang{at}cvmed.stanford.edu).

Objective: Mouse embryonic stem cells have demonstrated potential to restore infarcted myocardium after acute myocardial infarction. Although the underlying mechanism remains controversial, magnetic resonance imaging has provided reliable in vivo assessment of functional recovery after cellular transplants. Multimodal comparison of the restorative effects of mouse embryonic stem cells and mouse embryonic fibroblasts was performed to validate magnetic resonance imaging data and provide mechanistic insight.

Methods: SCID-beige mice (n = 55) underwent coronary artery ligation followed by injection of 2.5 x 105 mouse embryonic stem cells, 2.5 x 105 mouse embryonic fibroblasts, or normal saline solution. In vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells was evaluated by (1) in vivo pressure–volume loops, (2) in vivo bioluminescence imaging, and (3) ex vivo TaqMan (Roche Molecular Diagnostics, Pleasanton, Calif) polymerase chain reaction and immunohistologic examination.

Results: In vivo magnetic resonance imaging demonstrated significant improvement in left ventricular ejection fraction at 1 week in the mouse embryonic stem cell group. This finding was validated with (1) pressure–volume loop analysis demonstrating significantly improved systolic and diastolic functions, (2) bioluminescence imaging and polymerase chain reaction showing superior posttransplant survival of mouse embryonic stem cells, (3) immunohistologic identification of cardiac phenotype within engrafted mouse embryonic stem cells, and (4) polymerase chain reaction measuring increased expressions of angiogenic and antiapoptotic genes and decreased expressions of antifibrotic genes.

Conclusion: This study validates in vivo magnetic resonance imaging as an effective means of evaluating the restorative potential of mouse embryonic stem cells.

Abbreviations and Acronyms AMI = acute myocardial infarction; BLI = bioluminescence imaging; Ees = end-systolic elastance; EMax = maximal elastance; fluc = firefly luciferase gene; GFP = green fluorescent protein; LAD = left anterior descending coronary artery; LVEF = left ventricular ejection fraction; mEF = mouse embryonic fibroblast; mESC = mouse embryonic stem cell; MMP = matrix metalloproteinase; MRI = magnetic resonance imaging; NS = normal saline solution treatment; POD = postoperative day; PV = pressure–volume; RT-PCR = reverse transcriptase polymerase chain reaction; TM-PCR = TaqMan polymerase chain reaction; TNF {alpha} = tumor necrosis factor {alpha}; VEGF = vascular endothelial growth factor






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