Abstract
The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC–associated [18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI.
Highlights
Stem cell therapy has shown promise in patients with acute myocardial infarction (MI) or chronic ischemia [1]
We have demonstrated for the first time the feasibility of repetitive noninvasive positron emission tomography (PET)/computed tomography (CT) imaging with [18F]FEAU for long-term monitoring of Figure 4. [18F]FEAU PET/CT images observed in a pig 35 days after intramyocardial injection of sr39HSV1tk-mesenchymal stem cells (MSCs)
Our imaging studies showed a biphasic biodistribution of transplanted cells, with cell proliferation peaking about 34 days after delivery
Summary
Stem cell therapy has shown promise in patients with acute myocardial infarction (MI) or chronic ischemia [1]. The mechanisms by which cells transplanted into the myocardium provide benefits are not well defined, in part, because the longterm fate of injected cells is unknown. Clinically applicable imaging modalities are available for monitoring cardiac cell-based therapy [2,3,4], each has inherent disadvantages for studying the long-term fate of transplanted cells. Direct labeling of cells for single photon emission computed tomography (SPECT) and positron emission tomography (PET)/computed tomography (CT) is limited by the physical decay and biologic clearance of the radionuclide used [5,6]. Paramagnetic contrast agents and supramagnetic nanoparticles for magnetic resonance imaging (MRI) have the disadvantage of biologic clearance, but they can be sequestered in other cell types, limiting the duration of monitoring and increasing false positive results. A new approach—reporter gene imaging—has distinct advantages over direct labeling of cells
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