Abstract
Preclinical and clinical studies have shown that stem cells can promote the regeneration of damaged tissues, but therapeutic protocols need better quality control to confirm the location and number of transplanted cells. This study describes in vivo imaging while assessing reporter gene expression by its binding to a radiolabelled molecule to the respective receptor expressed in target cells. Five mice underwent human skeletal muscle-derived stem/progenitor cell (huSkMDS/PC EF1-HSV-TK) intracardial transplantation after induction of myocardial infarction (MI). The metabolic parameters of control and post-infarction stem progenitor cell-implanted mice were monitored using 2-deoxy-18F-fluorodeoxyglucose ([18F]-FDG) before and after double promotor/reporter probe imaging with 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]-FHBG) using positron emission tomography (PET) combined with computed tomography (CT). Standardized uptake values (SUVs) were then calculated based on set regions of interest (ROIs). Experimental animals were euthanized after magnetic resonance imaging (MRI). Molecular [18F]-FHBG imaging of myogenic stem/progenitor cells in control and post-infarction mice confirmed the survival and proliferation of transplanted cells, as shown by an increased or stable signal from the PET apparatus throughout the 5 weeks of monitoring. huSkMDS/PC EF1-HSV-TK transplantation improved cardiac metabolic ([18F]-FDG with PET) and haemodynamic (MRI) parameters. In vivo PET/CT and MRI revealed that the precise use of a promotor/reporter probe incorporated into stem/progenitor cells may improve non-invasive monitoring of targeted cellular therapy in the cardiovascular system.
Highlights
Abbreviations [18F]-FDG 2-Deoxy-18F-fluorodeoxyglucose [18F]-FHBG 9-(4-18F-Fluoro-3-[hydroxymethyl]butyl)guanine computed tomography (CT) Computed tomography HSV-TK Herpes simplex virus thymidine kinase huSkMDS/PCs Human skeletal muscle derived stem/progenitor cells left anterior descending artery (LAD) Left anterior descending artery LV Left ventricle myocardial infarction (MI) Myocardial infarction magnetic resonance imaging (MRI) Magnetic resonance imaging
There is a growing body of evidence that the use of stem/progenitor cells might positively support the function of damaged pathological tissues[9,10]; the majority of current methods for monitoring stem cell transplantation are based on post-mortem histological sampling at single time points
HuSkMDS/PCs were transduced with elongation factor 1 (EF1)-HSV-TK-Renilla luciferase (Renluc)-CMV-mCherry-T2A-PuroR lentiviral particles
Summary
Abbreviations [18F]-FDG 2-Deoxy-18F-fluorodeoxyglucose [18F]-FHBG 9-(4-18F-Fluoro-3-[hydroxymethyl]butyl)guanine CT Computed tomography HSV-TK Herpes simplex virus thymidine kinase huSkMDS/PCs Human skeletal muscle derived stem/progenitor cells LAD Left anterior descending artery LV Left ventricle MI Myocardial infarction MRI Magnetic resonance imaging. The post-infarction zone induces a process of cardiac remodelling, which results in major histological and morphological changes in both damaged and neighbouring healthy myocardial tissues[5]. Those who survive MI develop a fibrous scar that can have catastrophic consequences, such as dilated post-ischaemic cardiomyopathy and recurrent MIs6,7, potentially even leading to cardiac rupture and sudden death[8]. The goal of our study was to optimize non-invasive imaging of cellular stem/progenitor cell intervention based on an introduced reporter gene To control he biodistribution and retention of transplanted cells, we designed a multimodal reporter gene system. Monitoring by sensitive and high-resolution PET was possible due to stable gene expression, which in particular correlates with the number of viable c ells[12,13]
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