<i>In Vivo</i> magnetic resonance imaging of xenografted tumors using FTH1 reporter gene expression controlled by a tet-on switch

He, Xiangyi; Cai, Jinhua; Li, Hao; Liu, Bo; Qin, Yong; Zhong, Yi; Wang, Longlun; Liao, Yifan

doi:10.18632/oncotarget.12519

Cited by 11 publications

(11 citation statements)

References 46 publications

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“…In previous studies, we used ferritin heavy chain (FTH1) as an MRI reporter gene to detect transplanted MSCs in vivo and confirmed the feasibility of tracing cells in a sustained mode [ 18 , 20 ]. However, this reporter gene-based monitoring strategy could not be used to distinguish malignantly transformed cells from the originally transplanted stem cells.…”

Section: Introductionmentioning

confidence: 80%

“…The other is that the reporter gene should be expressed in a tumor-specific manner. Previous studies have revealed that FTH1, which can be transduced into stem cells and cause intracellular iron accumulation allowing for MRI signal change via overexpression, can be used as an ideal genetic MRI reporter for longitudinal monitoring of stem cells [ 18 – 20 , 32 ]. However, this strategy cannot be used to detect the occurrence of malignant stem cell transformation because the reporter gene is continuously expressed regardless of how the cells transform.…”

Section: Discussionmentioning

confidence: 99%

“…For the former method, intracellular magnetic nanoparticles can diminish with cell division, which limits the potential of this approach for long-term monitoring [ 15 – 17 ]. For the latter method, an MRI reporter gene can be expressed persistently and recruit iron particles into cells, which enables longitudinal monitoring of the labeled cells [ 18 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

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MRI detection of the malignant transformation of stem cells through reporter gene expression driven by a tumor-specific promoter

et al. 2021

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Background Existing evidence has shown that mesenchymal stem cells (MSCs) can undergo malignant transformation, which is a serious limitation of MSC-based therapies. Therefore, it is necessary to monitor malignant transformation of MSCs via a noninvasive imaging method. Although reporter gene-based magnetic resonance imaging (MRI) has been successfully applied to longitudinally monitor MSCs, this technique cannot distinguish the cells before and after malignant transformation. Herein, we investigated the feasibility of using a tumor-specific promoter to drive reporter gene expression for MRI detection of the malignant transformation of MSCs. Methods The reporter gene ferritin heavy chain (FTH1) was modified by adding a promoter from the tumor-specific gene progression elevated gene-3 (PEG3) and transduced into MSCs to obtain MSCs-PEG3-FTH1. Cells were induced to undergo malignant transformation via indirect coculture with C6 glioma cells, and these transformed cells were named MTMSCs-PEG3-FTH1. Western blot analysis of FTH1 expression, Prussian blue staining and transmission electron microscopy (TEM) to detect intracellular iron, and MRI to detect signal changes were performed before and after malignant transformation. Then, the cells before and after malignant transformation were inoculated subcutaneously into nude mice, and MRI was performed to observe the signal changes in the xenografts. Results After induction of malignant transformation, MTMSCs demonstrated tumor-like features in morphology, proliferation, migration, and invasion. FTH1 expression was significantly increased in MTMSCs-PEG3-FTH1 compared with MSCs-PEG3-FTH1. Prussian blue staining and TEM showed a large amount of iron particles in MTMSCs-PEG3-FTH1 but a minimal amount in MSCs-PEG3-FTH1. MRI demonstrated that the T2 value was significantly decreased in MTMSCs-PEG3-FTH1 compared with MSCs-PEG3-FTH1. In vivo, mass formation was observed in the MTMSCs-PEG3-FTH1 group but not the MSCs-PEG3-FTH1 group. T2-weighted MRI showed a significant signal decrease, which was correlated with iron accumulation in the tissue mass. Conclusions We developed a novel MRI model based on FTH1 reporter gene expression driven by the tumor-specific PEG3 promoter. This approach could be applied to sensitively detect the occurrence of MSC malignant transformation.

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Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MRI detection of the malignant transformation of stem cells through reporter gene expression driven by a tumor-specific promoter

et al. 2021

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“…Safety is a prerequisite for the application of the MRI tracing strategy for stem cells [ 33 , 34 ]. Previous studies demonstrated that although the use of SPIO labeling did not affect the proliferation activity of stem cells, it might reduce the osteogenic differentiation ability [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

In VitroNeural Differentiation of Bone Marrow Mesenchymal Stem Cells Carrying the FTH1 Reporter Gene and Detection with MRI

Qin

Liu

et al. 2018

BioMed Research International

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Magnetic resonance imaging (MRI) based on the ferritin heavy chain 1 (FTH1) reporter gene has been used to trace stem cells. However, whether FTH1 expression is affected by stem cell differentiation or whether cell differentiation is affected by reporter gene expression remains unclear. Here, we explore the relationship between FTH1 expression and neural differentiation in the differentiation of mesenchymal stem cells (MSCs) carrying FTH1 into neuron-like cells and investigate the feasibility of using FTH1 as an MRI reporter gene to detect neurally differentiated cells. By inducing cell differentiation with all-trans retinoic acid and a modified neuronal medium, MSCs and MSCs-FTH1 were successfully differentiated into neuron-like cells (Neurons and Neurons-FTH1), and the neural differentiation rates were (91.56±7.89)% and (92.23±7.64)%, respectively. Neuron-specific markers, including nestin, neuron-specific enolase, and microtubule-associated protein-2, were significantly expressed in Neurons-FTH1 and Neurons without noticeable differences. On the other hand, FTH1 was significantly expressed in MSCs-FTH1 and Neurons-FTH1 cells, and the expression levels were not significantly different. The R2 value was significantly increased in MSCs-FTH1 and Neurons-FTH1 cells, which was consistent with the findings of Prussian blue staining, transmission electron microscopy, and intracellular iron measurements. These results suggest that FTH1 gene expression did not affect MSC differentiation into neurons and was not affected by neural differentiation. Thus, MRI reporter gene imaging based on FTH1 can be used for the detection of neurally differentiated cells from MSCs.

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“…Ferritin is an ubiquitous and conserved protein complex that consists of 24 protein subunits of ferritin heavy chain (Fth) and ferritin light chains, and it is regarded as the primary intracellular iron-storage protein. Fth is also the major regulator of ferritin activity, which displays ferroxidase activity to promote iron oxidation and chelation, thus could be used as an T2 weighted image (T2WI) endogenous contrast agent [26][27][28][29][30][31][32]. Previous studies have evidenced that the transfection of Fth reporter gene with alpha-fetoprotein promoter (AFP-Fth) could induce a high expression level of ferritin only in the liver cancer cells, which therefore shows a potential ability in the diagnosis of HCC via MRI technique in vivo [33].…”

Section: Introductionmentioning

confidence: 99%

Sialic acid-engineered mesoporous polydopamine dual loaded with ferritin gene and SPIO for achieving endogenous and exogenous synergistic T2-weighted magnetic resonance imaging of HCC

Fan

Gao

et al. 2021

J Nanobiotechnol

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Background Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Magnetic resonance imaging (MRI) is one of the most effective imaging methods for the early diagnosis of HCC. However, the current MR contrast agents are still facing challenges in the early diagnosis of HCC due to their relatively low sensitivity and biosafety. Thus, the development of effective MR agents is highly needed for the early diagnosis of HCC. Results Herein, we fabricated an HCC-targeted nanocomplexes containing SPIO-loaded mesoporous polydopamine (MPDA@SPIO), sialic acid (SA)-modified polyethyleneimine (SA-PEI), and alpha-fetoprotein regulated ferritin gene (AFP-Fth) which was developed for the early diagnosis of HCC. It was found that the prepared nanocomplexes (MPDA@SPIO/SA-PEI/AFP-Fth) has an excellent biocompatibility towards the liver cells. In vivo and in vivo studies revealed that the transfection of AFP-Fth gene in hepatic cells significantly upregulated the expression level of ferritin, thereby resulting in an enhanced contrast on T2-weighted images via the formed endogenous MR contrast. Conclusions The results suggested that MPDA@SPIO/SA-PEI/AFP-Fth had a superior ability to enhance the MR contrast of T2-weighted images of tumor region than the other preparations, which was due to its HCC-targeted ability and the combined T2 contrast effect of endogenous ferritin and exogenous SPIO. Our study proved that MPDA@SPIO/SA-PEI/AFP-Fth nanocomplexes could be used as an effective MR contrast agent to detect HCC in the early stage.

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In Vivo magnetic resonance imaging of xenografted tumors using FTH1 reporter gene expression controlled by a tet-on switch

Cited by 11 publications

References 46 publications

MRI detection of the malignant transformation of stem cells through reporter gene expression driven by a tumor-specific promoter

MRI detection of the malignant transformation of stem cells through reporter gene expression driven by a tumor-specific promoter

In VitroNeural Differentiation of Bone Marrow Mesenchymal Stem Cells Carrying the FTH1 Reporter Gene and Detection with MRI

Sialic acid-engineered mesoporous polydopamine dual loaded with ferritin gene and SPIO for achieving endogenous and exogenous synergistic T2-weighted magnetic resonance imaging of HCC

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