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

Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Journal of the American College of Cardiology (Impact Factor: 16.5). 11/2006; 48(10):2116-24. DOI: 10.1016/j.jacc.2006.06.073
Source: PubMed


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).
Although intramyocardial injection of allogeneic MSCs improves global cardiac function after MI, the mechanism(s) underlying this phenomenon are incompletely understood.
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.
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 mum vs. 12.6 +/- 0.2 mum, p < 0.05).
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.

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    • "In addition, a recent report revealed that both MSCs and BM-derived stem cells have been associated with calcification and probably ossification of the heart in a murine model of MI [108]. In contrast to these observations, numerous large-animal preclinical studies displayed the safety of MSCs therapy and are devoid of tumor formation or ectopic tissue growth [80, 81, 83–87, 90, 91, 94]. Moreover, data from early-phase human studies using MSCs showed no evidence of ectopic tissue growth [103–105]. "
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    ABSTRACT: Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), an estimate of 17.3 million people died from CVDs in 2008 and by 2030, the number of deaths is estimated to reach almost 23.6 million. Despite the development of a variety of treatment options, heart failure management has failed to inhibit myocardial scar formation and replace the lost cardiomyocyte mass with new functional contractile cells. This shortage is complicated by the limited ability of the heart for self-regeneration. Accordingly, novel management approaches have been introduced into the field of cardiovascular research, leading to the evolution of gene- and cell-based therapies. Stem cell-based therapy (aka, cardiomyoplasty) is a rapidly growing alternative for regenerating the damaged myocardium and attenuating ischemic heart disease. However, the optimal cell type to achieve this goal has not been established yet, even after a decade of cardiovascular stem cell research. Mesenchymal stem cells (MSCs) in particular have been extensively investigated as a potential therapeutic approach for cardiac regeneration, due to their distinctive characteristics. In this paper, we focus on the therapeutic applications of MSCs and their transition from the experimental benchside to the clinical bedside.
    06/2012; 2012(1):646038. DOI:10.1155/2012/646038
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    • "However, this difference can be attributed to methodological discrepancies regarding time of transplantation (acute versus chronic resp.) or followup (1 versus 6 months). Equivalent and importantly, results from clinically relevant large animal models of MI in which allogenic cells have been employed have revealed either positive [99, 100] or no functional outcome [79]. In contrast, when autologous ADSC or BM-MSC are used [72, 83, 101, 102], reports have shown a robust and consistent functional recovery after cell transplantation. "
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    ABSTRACT: In recent years, the incredible boost in stem cell research has kindled the expectations of both patients and physicians. Mesenchymal progenitors, owing to their availability, ease of manipulation, and therapeutic potential, have become one of the most attractive options for the treatment of a wide range of diseases, from cartilage defects to cardiac disorders. Moreover, their immunomodulatory capacity has opened up their allogenic use, consequently broadening the possibilities for their application. In this review, we will focus on their use in the therapy of myocardial infarction, looking at their characteristics, in vitro and in vivo mechanisms of action, as well as clinical trials.
    01/2012; 2012(2):175979. DOI:10.1155/2012/175979
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    • "Digital images were taken for morphometric analysis of LV area, infarct size, and thickness, using IPLab software (Scanalytics, Rockville, MD). Infarct size was defined as a thinned and pale region of the anterior LV wall [30] and did not account for areas of viable tissue. Myocardial tissue for paraffin embedding was taken from the basal, mid, and apical-cavity levels. "
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    ABSTRACT: Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model. MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI. At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41 ± 1% vs. 33 ± 1%, p < 0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy. Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.
    Cardiovascular Drugs and Therapy 12/2010; 24(5-6):409-20. DOI:10.1007/s10557-010-6263-7 · 3.19 Impact Factor
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