Manganese‐Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri‐Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia–Reperfusion Model

Abstract

BackgroundThe exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.Methods and ResultsTwelve adult swine underwent ischemia–reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI–positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05).ConclusionsThe positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.

Seeing What We Build—The Need for New Imaging Techniques in Myocardial Regeneration

“…A strong correlation was seen between increased viability in the PIR and cell survival via PET imaging of the thymidine kinase reporter gene. However, consistent with prior studies of mesenchymal stem cells, no evidence of cardiomyocyte differentiation was seen …”

“…The response to intramyocardial injection of human amniotic mesenchymal stem cells was examined in their study. Cell injection decreased the size of the infarct core and the PIR, and resulted in lower end‐diastolic volumes and higher EF . A strong correlation was seen between increased viability in the PIR and cell survival via PET imaging of the thymidine kinase reporter gene.…”

“…Advanced imaging techniques to characterize many of these processes have been developed (Figure) and several are poised for use in humans. In the current issue of JAHA , Dash and colleagues add to this armamentarium with an elegant approach involving dual‐contrast magnetic resonance imaging (MRI) and positron emission tomography (PET) of a reporter probe . The value of this and other advanced imaging approaches is discussed below.…”

A rapid T1 mapping method for assessment of murine kidney viability using dynamic manganese‐enhanced magnetic resonance imaging

“…Previously, it has been shown that a systemic administration of MnCl 2 led to comparable Mn 2+ accumulation in heart and kidney of mice . Similar to the heart , the ability of Mn 2+ uptake and retention in kidney might be affected by its viability. Therefore, we sought to explore the ability of dynamic MEMRI to detect and delineate renal regional responses to ischemia in a mouse model of unilateral RAS with the aid of a newly developed rapid T 1 mapping method, MSRFSE.…”

Enhanced Device for Cell Delivery to the Myocardium: Validation in Swine Hearts

“…Although transendocardial cell infusion is associated with a low level of cell engraftment, some methods have been proposed to increase the engraftment ratio of the transplanted cells [24][25][26][27]. MSCs are thought to be particularly effective for regeneration therapy owing to their paracrine effect even when the cell survival rate is low [28][29][30], because MSCs secrete various vascularization factors such as vascular endothelial growth factor and hepatocyte growth factor [31]. In addition, various other agents besides cells have been infused using endocardium infusion devices, such as proteins or genes [32,33].…”