clear cell renal cell carcinoma (ccRcc) is the most common kidney cancer. prognosis for ccRcc is generally poor since it is largely resistant to chemo-and radiotherapy. Many studies suggested that cancer stem cells/tumor initiating cells (CSCs/TICs) are responsible for development of tumor, disease progression, aggressiveness, metastasis and drug resistance. However, tumorigenic potential of CSCs/ tics isolated from established Rcc cell lines-basic ccRcc research model-has never been investigated in vivo. CD105+, CD105−, CD44+ and CD44− as well as CD44−/CD105− CD44+/CD105+ and CD44−/ CD105+ cells were isolated from Caki-1 RCC cell line, confirming coexistence of multiple subpopulations of stem-related phenotype in stable cell line. Sorted cells were injected subcutaneously into noD SciD mice and tumor growth was monitored with MRi and pet/ct. tumor growth was observed after implantation of CD105+, CD44+, CD44−, CD44−/CD105+ and CD44−/CD105− but not CD105− or CD44+/CD105+. Implantation of CD44−/CD105− cells induced tumors that were characterized by longer T1 and distinct metabolic pattern than other tumors. All the tumors were characterized by low uptake of [18F]FDG. CD105+ and CD44− tumors expresses Nanog and Oct-4, while CD44− tumors additionally expressed endothelial cell marker-CD31. Renal cell carcinoma (RCC), is the 10th malignancy worldwide and the most frequent type of kidney cancer in adults. Each year in Europe approximately 88 400 patients are diagnosed with RCC; the incidence and mortality of RCC are rising at a rate of 2-3% per decade, therefore novel therapies directed against RCC are needed. At the same time despite advancements in diagnostic techniques, up to 30% of newly diagnosed patients already present with metastases, and a large portion of patients that undergo surgical treatment experience the RCC recurrence, therefore drugs targeted against metastasis initiating cells would be of great interest in the future 1,2. Cancer stem cells (CSCs) are characterized by the potential to self-renew, high tumorigenicity in nude mice and the ability to efficiently reconstitute all tumor subpopulations and primary tumor phenotype 3-5. CSCs are also responsible not only for cancer development, but also for disease recurrence, progression and metastatic spread, together with cancer aggressiveness, including treatment resistance such as chemo/radiotherapy, and targeted treatment 6,7 , therefore basic research with careful model selection to understand their biology is mandatory to define novel potential therapeutic targets for all RCC subtypes 8,9 .
Current treatment protocols for myocardial infarction improve the outcome of disease to some extent but do not provide the clue for full regeneration of the heart tissues. An increasing body of evidence has shown that transplantation of cells may lead to some organ recovery. However, the optimal stem cell population has not been yet identified. We would like to propose a novel pro-regenerative treatment for post-infarction heart based on the combination of human skeletal myoblasts (huSkM) and mesenchymal stem cells (MSCs). huSkM native or overexpressing gene coding for Cx43 (huSKMCx43) alone or combined with MSCs were delivered in four cellular therapeutic variants into the healthy and post-infarction heart of mice while using molecular reporter probes. Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) performed right after cell delivery and 24 h later revealed a trend towards an increase in the isotopic uptake in the post-infarction group of animals treated by a combination of huSkMCx43 with MSC. Bioluminescent imaging (BLI) showed the highest increase in firefly luciferase (fluc) signal intensity in post-infarction heart treated with combination of huSkM and MSCs vs. huSkM alone (p < 0.0001). In healthy myocardium, however, nanoluciferase signal (nanoluc) intensity varied markedly between animals treated with stem cell populations either alone or in combinations with the tendency to be simply decreased. Therefore, our observations seem to show that MSCs supported viability, engraftment, and even proliferation of huSkM in the post-infarction heart.
Cardiovascular diseases (CVD), with myocardial infarction (MI) being one of the crucial components, wreak havoc in developed countries. Advanced imaging technologies are required to obtain quick and widely available diagnostic data. This paper describes a multimodal approach to in vivo perfusion imaging using the novel SYN1 tracer based on the fluorine-18 isotope. The NOD-SCID mice were injected intravenously with SYN1 or [18F] fluorodeoxyglucose ([18F]-FDG) radiotracers after induction of the MI. In all studies, the positron emission tomography–computed tomography (PET/CT) technique was used. To obtain hemodynamic data, mice were subjected to magnetic resonance imaging (MRI). Finally, the biodistribution of the SYN1 compound was performed using Wistar rat model. SYN1 showed normal accumulation in mouse and rat hearts, and MI hearts correctly indicated impaired cardiac segments when compared to [18F]-FDG uptake. In vivo PET/CT and MRI studies showed statistical convergence in terms of the size of the necrotic zone and cardiac function. This was further supported with RNAseq molecular analyses to correlate the candidate function genes’ expression, with Serpinb1c, Tnc and Nupr1, with Trem2 and Aldolase B functional correlations showing statistical significance in both SYN1 and [18F]-FDG. Our manuscript presents a new fluorine-18-based perfusion radiotracer for PET/CT imaging that may have importance in clinical applications. Future research should focus on confirmation of the data elucidated here to prepare SYN1 for first-in-human trials.
Cardiovascular diseases (CVD) is a collective term describing a range of conditions that affect the heart and blood vessels. Due to the varied nature of the disorders, distinguishing between their causes and monitoring their progress is crucial for finding an effective treatment. Molecular imaging enables non-invasive visualisation and quantification of biological pathways, even at the molecular and subcellular levels, what is essential for understanding the causes and development of CVD. Positron emission tomography imaging is so far recognized as the best method for in vivo studies of the CVD related phenomena. The imaging is based on the use of radioisotope-labelled markers, which have been successfully used in both pre-clinical research and clinical studies. Current research on CVD with the use of such radioconjugates constantly increases our knowledge and understanding of the causes, and brings us closer to effective monitoring and treatment. This review outlines recent advances in the use of the so-far available radioisotope markers in the research on cardiovascular diseases in rodent models, points out the problems and provides a perspective for future applications of PET imaging in CVD studies.
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.
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