Objectives
To quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods using Positron Emission Tomography (PET).
Background
Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery.
Methods
CDCs derived from syngeneic, male Wistar Kyoto (WK) rats were labeled with 18FDG and injected intramyocardially into the ischemic region of female WK rats following permanent left coronary artery ligation.
The effects of fibrin glue, bradycardia (adenosine) and cardiac arrest were examined. 18FDG PET was performed for quantification of cell retention. Quantitative PCR for the male-specific SRY gene was performed to validate the PET results.
Results
Myocardial retention of cells suspended in PBS 1 hr after delivery was 17.6±11.5% by PCR and 17.8±7.3% by PET. When CDCs were injected immediately following induction of cardiac arrest, retention was increased to 75.6±18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4±5.3%). A similar increase in CDC retention was observed following epicardial application of fibrin glue at the injection site (37.5±8.2%). PCR revealed a significant increase in 3 week cell engraftment in the fibrin glue animals (22.1±18.6% vs 5.3±3.1%, for fibrin glue and PBS respectively).
Conclusions
In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with fibrin glue or lowering ventricular rate by adenosine may be clinically translatable methods for improving stem cell engraftment in a beating heart.
Brown adipose tissue (BAT) densities assessed as CT Hounsfield units (HUs) were evaluated in a rodent model and in patients to determine whether HUs changed in relation to BAT activity. Methods: Serial 18 F-FDG PET/CT was performed on rats under both room temperature control conditions and after 4 h of coldstimulation, which is known to activate BAT. The maximum standardized uptake values and CT HUs of BAT were measured, and tissues were examined in the laboratory. Image records from cancer patients who underwent PET/CT were reviewed, and 23 patients were identified who displayed both high and low 18 F-FDG uptake into BAT on serial 18 F-FDG PET/CT scans. The maximum standardized uptake values and CT HUs of BAT were compared in these scans. Results: The mean (6SD) CT HUs of cold-activated BAT (212.4 6 22.4) were significantly higher than those (227.9 6 9.6) of the controls in the rat model. The CT HUs of BAT (271.6 6 18.0) in the patients with high 18 F-FDG uptake were significantly higher than those (2104.4 6 16.8) of the patients with low 18 F-FDG uptake . A decrease in relative lipid content is seen in activated BAT in rats on histology. Conclusion: The CT HUs of BAT increased in activated conditions in both animals and patients, likely because of lipid consumption by activated BAT.
Objectives
We examined the sodium-iodide symporter (NIS) which promotes in vivo cellular uptake of 99mTc or 124I, as a reporter gene for cell tracking by SPECT or PET imaging.
Background
Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo.
Methods
The human NIS cDNA was transduced into rat cardiac-derived stem cells (rCDCs) using lentiviral vectors. Rats were injected intra-myocardially with up to 4 million NIS+-rCDCs immediately following LAD ligation. Dual isotope SPECT (or PET) imaging was performed, using 99mTc (or 124I) for cell detection and 201Tl (or 13NH3) for myocardial delineation. In a subset of animals, high resolution ex vivo SPECT scans of explanted hearts were obtained to confirm that in vivo signals were derived from the cell injection site.
Results
NIS expression in rCDCs did not affect cell viability and proliferation. NIS activity was verified in isolated transduced cells by measuring 99mTc uptake. NIS+ rCDCs were visualized in vivo as regions of 99mTc or 124I uptake within a perfusion deficit in the SPECT and PET images, respectively. Cells could be visualized by SPECT up to day 6 post-injection. Ex vivo SPECT confirmed that in vivo
99mTc signals were localized to the cell injection sites.
Conclusion
Ectopic NIS expression allows non invasive in vivo stem cell tracking in the myocardium, using either SPECT or PET. The general approach shows significant promise in tracking the fate of transplanted cells participating in cardiac regeneration, given its ability to observe living cells using clinically-applicable imaging modalities.
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