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Reporter Genes for Brain Imaging: History
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Contributor: Tianxin Gao ,
Pei Wang
, Teng Gong ,
Ying Zhou
, Ancong Wang , Xiaoying Tang , Xiaolei Song , Yingwei Fan

The use of molecular imaging technologies for brain imaging can not only play an important supporting role in disease diagnosis and treatment but can also be used to deeply study brain functions. With the support of reporter gene technology, optical imaging has achieved a breakthrough in brain function studies at the molecular level. Reporter gene technology based on traditional clinical imaging modalities is also expanding. By benefiting from the deeper imaging depths and wider imaging ranges now possible, these methods have led to breakthroughs in preclinical and clinical research.

  • reporter gene
  • MRI
  • radionuclide imaging
  • brain imaging
  • PET
  • SPECT

1. Introduction

Molecular imaging is an imaging technique that visualizes, characterizes, and measures biological processes in vivo at the molecular and cellular levels [1]. Reporter gene imaging is a critical technical route for molecular imaging, which introduces or expresses imaging agents into cells through so-called reporter genes. Reporter genes are those genes that, when introduced into target cells (e.g., brain tissues, cancer, and circulating white cells), produce a protein receptor or enzyme that binds, transports, or traps a subsequently injected imaging probe, which becomes the contrast agent for reporter gene imaging [2]. Reporter gene imaging is developing very rapidly for monitoring cell therapy and gene therapy by providing critical information on the biodistributions, magnitudes, and durations of viral gene expressions. Imaging the brains of large animals or humans on a large scale has become the next challenge of reporter gene imaging.
Among multiple imaging modalities, fluorescence reporter genes have drawn great attention; however, penetration depths limit their in vivo application [3]. Recently, other imaging modalities, including magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and ultrasound (US) imaging, have been explored in the field of reporter genes [2]. The advantages of genetically encoded fluorescent imaging are high spatiotemporal resolution, high sensitivity, and high molecular specificity, while some conventional imaging modalities that use modern reporter gene indicators are effective in clearly examining the brains of larger subjects in deep organs and on large scales. Compared with optical reporter gene imaging, other types of reporter gene imaging have a variety of properties. For the imaging depths and scales, clinical imaging techniques provide better performance, while fluorescence reporters are excellent in terms of their temporal–spatial resolution, noninvasiveness, molecular and cell specificity, and sensitivity.
Brain imaging includes imaging of diseases, such as neurodegenerative disease and glioma, and foundational brain research, which can be divided into two categories: macroscopic, noninvasive human cognitive neuroscience and invasive reductionist neurobiology [4]. Reporter gene base brain imaging includes both of these categories. Nonoptical imaging modalities are commonly used in clinics, which means that such studies involve direct human applications.

2. Principle of Reporter Gene Imaging

The two basic elements of reporter gene imaging consist of reporter genes and their respective imaging probes (which are also the referred to as imaging agents, substrates, or imaging reporters in other references). The accumulation of imaging probes directly depends on the protein products of reporter gene expression, thereby imaging the reporter gene. Because it only monitors living cells, it can accurately provide important information such as that of survival, proliferation, migration, differentiation, and functional integration of transplanted cells in vivo [1][5][6].

2.1. Reporter Gene Imaging with MRI

MRI employs the resonance properties of atomic nuclei subjected to strong magnetic fields and radiofrequency pulses to generate signals and reconstruct images. MRI reporter genes can directly or indirectly produce magnetic resonance contrast signals that are based on the expressions of coding enzymes, receptors, metalloproteins, etc., which can specifically combine with MRI contrast agent [7][8][9][10]. MRI reporter genes can be used to longitudinally monitor the cell migration process and gene expressions by using noninvasive imaging [11]. The main types of existing MRI reporter genes include reporter genes that encode enzymes (e.g., tyrosinase), reporter genes that encode receptors on cells (e.g., transferrin receptor (TfR)), endogenous reporter genes (e.g., ferritin and aquaporin 1 (AQP1)), and reporter genes that express CEST-detectable proteins (e.g., lysine rich-protein (LRP)) [12].
The most classic contrast agent for MRI reporter genes is iron. As a ubiquitous protein in the cells of various organisms, ferritin is assembled by two subunits, a heavy chain and a light chain. The proportions of light and heavy chains vary in different tissues. The ferritin heavy chain (FTH1) contains ferrous oxidase and can combine with iron oxide to transform unstable Fe2+ into stable, insoluble, and nontoxic Fe3+ forms. The light chain mainly increases the activity of FTH1 and stabilizes ferritin. Ferritin can specifically bind to iron, which results in accumulations of intracellular iron particles and decreases in T2 signals [13], and it is one of the most commonly used reporter genes in MRI. The transferrin receptor (TfR) is another commonly used MRI reporter gene. TfR can bind to transferrin and transfer iron into cells via endocytosis, thus reducing the T2 relaxation time [11][14]. Lysine-rich protein (LRP) is an artificially designed gene. Due to the uniquely high chemical exchange rate of poly-l-lysine, LRP can be used as a reporter gene in chemical exchange saturation transfer (CEST) MRI [15][16]. The CEST mechanism occurs because exchangeable protons have chemical shifts that are different from water. These protons are selectively saturated and exchanged with water molecules, thus reducing the water signal. Magnetic resonance diffusion-weighted imaging (DWI) is an imaging method that uses MRI to observe the microdiffusion movements of water molecules in living tissues. It can noninvasively image the structures and physiological functions of living brain tissues. The apparent diffusion coefficient (ADC) is used to describe the diffusion rate of water molecules in DWI. A positive correlation exists between them. When water molecules with freer diffusion are dephasing, the level of signal loss is greater, the signal is weaker, and it appears darker in DWI, and vice versa [17][18]. Aquaporins mediate the selective exchange of water-conducting molecules across plasma membranes in many cell types, and their expressions are related to water diffusivity and DWI signals in several disease states [19][20]. Previous studies have shown that overexpression of aquaporin can increase tissue water diffusivity without affecting viability, and contrasts are observed in diffusion-weighted MRI [21].

2.2. Reporter Gene Imaging with Radionuclides

Radionuclide imaging refers to SPECT and PET. SPECT detects gamma rays that are produced by the decay of the radioactive isotopes used in imaging, and it has been developed to elucidate the basic molecular neurodegeneration mechanism in PD, AD, and drug addiction, as well as to improve therapeutic strategies with minimum adverse effects. PET uses the annihilation of positrons (emitted by decaying radioisotopes in the imaging agent) and electrons to generate 510 keV collinear photons, which are detected simultaneously to generate a three-dimensional map of radioactivity distributions in the body [22]. Radionuclide imaging has very high sensitivity and good penetration ability in tissues, and it can be used in clinical practice. It has been widely used for noninvasive tracing and monitoring of living cells.
PET imaging of reporter gene expression utilizes reporter gene imaging agents that are labeled by positron radionuclides. Currently, there are three types of commonly used radionuclide reporter gene imaging systems based on enzymes, receptors, and transporters [22][23]. The most common reporter genes of enzymes are herpes simplex virus 1 thymine kinase (HSV1-tk) [6] and human Δ-mitochondrial thymine kinase type 2 (hΔtk2) [24]. The most common reporter genes are human somatostatin receptor type 2 (hSSTR2) [25] and dopamine D2 receptor (D2R) [26]. The most common reporter genes of transporters are human sodium–iodide symporter (hNIS) [27] and human norepinephrine transporter (hNET) [2][28].
One of the first and hence most intensively studied reporter genes, HSV1-tk, is also a suicide gene that adds an extra layer of control to ensure safety. NIS imaging is the most mature reporter gene imaging method used in human clinical trials and is more sensitive and longer lasting than HSV1-tk.
The SPECT imaging system was developed to elucidate the basic molecular neurodegeneration mechanism in PD, AD, and drug addiction, as well as to improve therapeutic strategies with minimum amounts of adverse effects. PET imaging can provide diagnosis and treatment guidance for tumors and cardiovascular and brain diseases. PET imaging of reporter gene expressions is capable of monitoring gene and cell therapy [22]. In brain studies, brain cancer and neurodegenerative disorders are the major diseases diagnosed and monitored by reporter gene expression PET imaging, as discussed thoroughly in Section 3.2.

3. Reporter Gene Imaging in Brain Studies

3.1. Brain Imaging of Reporter Genes with MRI

In view of the diversity, high resolution, and noninvasive nature of MRI, MRI imaging of the brain can be used in a variety of applications, such as observing the process of virus infection through in vivo imaging, longitudinally monitoring cell migration and proliferation during cell therapy, noninvasive detection of neural connections, and monitoring neurogenesis.
Visualization of neural networks helps provide a better understanding of the mechanisms of some brain functions and brain diseases. In the study of Wang et al. [29], vesicular stomatitis virus (VSV), a neurovirus that can spread sequentially in synaptic networks, was used to carry chimeric genes that encode ferritin and enhanced green fluorescent protein (EGFP). After recombinant VSV (rVSV) was injected into the somatosensory cortex (SC) of mice, the structural nerve connections were detected by MRI and fluorescence imaging. However, due to the high toxicity of VSV, mice infected with rVSV cannot survive for long periods, and in vivo MRI research is not allowed. In another study conducted by the team [30], hypotoxicity virus adeno-associated virus (AAV) was used as a vector to integrate the ferritin coding gene to obtain a ferritin coding viral vector (e.g., rAAV2-retro–CAG–Ferritin), which was injected into the caudate putamen (CPu) of mice to achieve noninvasive detection of neural networks in vivo. The CPu connection area was displayed by MRI at different time points after rAAV2-retro–CAG–ferritin injection. The team then focused on describing the activity of astrocytes, which are a major component of the central nervous system. They used the EGFP–AQP1 fusion gene of EGFP and aquaporin 1 (AQP1) as the reporter gene, detected astrocytes by fluorescence imaging and diffusion-weighted MRI, and established a new technique for the noninvasive detection of astrocytes in vivo for the first time [31]. In the newly published work [32] of the team, a tool virus rAAV-retro–AQP1–EGFP expressing nonmetallic magnetic resonance reporter gene AQP1 was prepared and used for in vivo brain-wide neural network detection. Three weeks after microinjection of virus rAAV-retro–AQP1–EGFP into the CPU brain area of mice, the changes in magnetic resonance signals in multiple brain regions (CPU, Ctx, BLA, Ins, Tha, HIP, etc) were observed by diffusion-weighted MRI, and the rapid imaging of specific brain region-related brain networks was successfully realized (increase from 60 days [30] to 21 days). The project also combined with the Cre–loxP system to prepare a brain network expressing Cre-dependent AQP1-related tool virus rAAV-retro–DIO–AQP1–EGFP for in vivo detection of specific neuronal types in specific brain regions. This strategy provides a solid foundation for the visualization of neural networks in rodents and nonhuman primates.
Mesenchymal stem cells (MSCs) can cross the blood–brain barrier and tend to accumulate in tumors [33]; hence, they can be developed as cell carriers to treat gliomas [34][35][36]. Longitudinal in vivo monitoring of the migration and fate of MSCs is very important for the development of MSCs as cell carriers. Cao et al. [37] used a lentivirus as a vector to carry the ferritin heavy chain (FTH) and EGFP genes and transferred it to MSCs. MCSs expressing reporter genes were injected into a rat glioma model using different injection methods (e.g., arterial injection, intravenous injection, and stereotactic injection), and the homing and migration behaviors of MSCs were detected by MRI. The results showed that arterial injections of MSCs had a clear ability to treat glioma. MRI based on the ferritin reporter gene can be used to trace the tendency of MSCs to accumulate in glioma in vivo. Mao et al. [38] constructed MSCs with high expressions of interferon-β (IFNβ) and FTH in a similar manner. MRI was used to evaluate whether MSCs can be used as cell carriers to carry IFNβ to treat brain tumors, which provides a new option for treating brain tumors. Studies have shown that FTH-based MRI can monitor this treatment process.
MRI reporter genes are also used to study brain viral infections and for brain tumor imaging. Oncolytic viruses can be used to treat malignant tumors, such as glioblastoma [39][40]. The infection process is expected to be observed by MRI. In clinical trials, Christian et al. [15] integrated the lysine-rich protein (LRP) gene into a herpes simplex virus-derived oncolytic virus G47∆ virus. CEST MRI was used to detect gliomas in rats before and 8 h after injection of G47∆-LRP or a control G47∆-empty virus. The contrast increased in tumors of CEST images after infection with G47∆-LRP virus. This shows that LRP can be used as a reporter gene for real-time monitoring of virus transmission, but the highly repeated gene sequence of LRP may lead to DNA recombination events and expression of a series of truncated LRP protein fragments, which limits the sensitivity of CEST imaging. To address this problem, Perlman et al. [41] redesigned an LRP reporter (rd LRP) without DNA repeat sequences and improved its CEST MRI contrast.
Additional innovative studies have been reported. Hyla et al. [42] developed a system called GeneREFORM, calculated and designed a group of two-color reporter genes and probes, and established a two-color gene imaging system. With the aid of existing MRI technology, GeneREFORM can accurately locate and achieve noninvasive two-color imaging of multiple genes in the deep tissues of living animals. The GeneREFORM system is also applicable to nontumor models.
There are also potential MRI reporter genes that can be used for brain imaging, notably gas vesicles (GVs). GVs [43] are gas-filled protein nanostructures that are originally located in the cells of some bacteria and archaea that regulate cell buoyancy in aqueous environments [44][45]. GVs are gene-encoded nanoscale probes composed of the primary structural protein, GvpA, the optional external scaffolding protein, GvpC, for structure reinforcement, and several secondary proteins that function as essential minor constituents or chaperones [46]. GVs consists of external hydrophilic and internal hydrophobic protein structures, which cause their interiors to form gas cavities filled with gas that is separated from the surrounding medium and realizes the simultaneous free exchange of internal and external gas [47]. In the biological world, photosynthetic bacteria use the contents of gas contained in vesicles to regulate buoyancy and accomplish their own floating behavior. The magnetic susceptibility of GVs is quite different from that of water, which can produce large contrasts in magnetic resonance imaging, even at sub-nanomolar concentrations. The gas cavities of the vesicles can scatter sound waves and produce ultrasonic contrasts. When the pressure on the air wall is greater than the threshold, the vesicles collapse; thus, background-free imaging can be achieved by acoustically modulated magnetic resonance imaging. The mechanical and surface characteristics of GvpC can be genetically modified by replacing the natural external GvpC with its recombinant variant, thus changing its magnetic susceptibility and collapse pressure, with the potential to obtain multichannel imaging. George et al. [48] showed that background-free imaging can be achieved by acoustic modulation MRI after injection of GVs into the striatum of mice. When using the same method, MRI contrast could not be obtained after injections of phosphate buffer without GVs. These results indicate that GVs are expected to become an MRI reporter gene for brain imaging.
Vasoactive peptides are another potential MRI reporter gene for use in brain imaging. Their expression can cause vasodilation and facilitate hemodynamic imaging. Designed probes based on vasodilating peptides can image brain regions [49] and can be used to detect important molecules in the brain, such as neurochemicals [50]. Its use provides the potential to examine a wide variety of molecular phenomena in the brain and other organs.

3.2. Brain Imaging of Reporter Genes with Radionuclide

The majority of radionuclide imaging studies in the brain are related to cell/gene therapy monitoring. They must be able to address challenges such as penetrating the blood–brain barrier (BBB), imaging in regions of high endogenous gene expressions in the central nervous system (CNS), low specificity, and endogenous expressions of reporter genes in microglia [51]. Shimojo [52] used bacterial dihydrofolate reductase (ecDHFR) as a reporter gene and [18F]FE-TMP as an imaging probe, which functioned as a dual probe in both fluorescence and PET imaging to image the CNS system. As a result, PET could analyze mammalian brain circuits at the molecular level.
SPECT and PET are useful in neuroscience research, especially in studies of neurodegeneration and neuro-oncology [53][54]. Stem = cell therapy offers new strategies for treating neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis caused by the loss of different types of neurons and glial cells in the brain. SPECT [55][56] and PET [51][57][58] can trace and evaluate the function of stem cells in the nervous system [59]. Multimodality imaging using several reporter genes used dual [60][61] or triple [62] fusion reporter vectors to enable high-sensitivity detection of cells in living animals. A dual-membrane protein positron and gamma-imaging reporter system using sodium iodide symporter and mutant dopamine D-2 receptor transgenes was developed for brain tumor detection.
HSV1-TK using the imaging probe, FHBG, has been used in glioma treatments to monitor chimeric antigen receptor (CAR) T-cell biodistributions and proliferation [63][64]. A study of the imaging probe, FIAU, in patients showed that FIAU cannot penetrate an intact BBB [53][65]. After gene therapy, substantial levels of FIAU may be detected within areas of BBB disruption; hence, clinically relevant levels of HSV-1-tk gene expression in brain tumors can be detected [65]. FBAU [66] is another promising imaging probe that has been studied in glioma imaging based on a mouse model.
In addition to glioma, bone marrow stem cells (BMSCs) used in experimental middle cerebral artery occlusion (MCAO) rat models have been imaged with a reporter gene–probe system [55], consisting of the HSV1-tk and [131I]FIAU pair. BMSCs were introduced into MCAO rat models via local injections into the brain or via injections into the lateral ventricle, carotid artery, or tail vein. The quantity of injected dose per gram in infarcted brain tissue in rats receiving injections into the brain was significantly higher than that in rats receiving injections elsewhere. No differences were seen in the other cell transplantation groups. SPECT imaging with [131I]FIAU 24 h after injection provides peak target-to-nontarget count ratios. Neural stem cells have also been traced by SPECT [56]. The human sodium iodide symporter (hNIS) has been used as a reporter gene to track neural stem cells after transplantation in the brains of rats by using SPECT/CT imaging with technetium-99m to indicate the effectiveness and lack of interference with neural stem cell functioning. Dopamine type 2 receptor (D2R) and its mutant (D2R80A) have been used for neural stem cell tracing in the central nervous system. [11C]N-methylspiperone microPET has been proven useful in imaging neural stem-cell-induced D2R expressions in a rat model of traumatic brain injury [57]. It has also been proven in athymic rats that D2R80A is an effective reporter gene for human mesenchymal stem-cell detection in vivo [58]. In another study with mice and cats, a separate adeno-associated virus type 1 vector with identical gene expression control elements was co-injected with the D2R80A vector. This dual-vector approach allows the D2R80A gene to be used with any therapeutic gene and to be injected into a single site for monitoring [67].
The BBB penetration ability of imaging probes hampers the usage of reporter gene imaging. FHBT was studied to improve BBB permeability [68], but there were no significant improvements compared with the traditional probe, FHBG. It was demonstrated that the novel scaffold proposed supports the development of a new imaging probe with better BBB permeability for HSV1-tk and its mutant in the future. This imaging probe combined with reporter genes other than HSV1-TK provides a better solution for crossing the intact BBB. The human-type 2 cannabinoid receptor (hCB(2)) related ligand, [11C]GW405833, for example, is readily distributed across the BBB. hCB(2)(D80N) was locoregionally overexpressed in the rat striatum by stereotactic injections of lentiviral and adeno-associated viral vectors. Kinetic PET revealed specific and reversible CB(2) binding of [11C]GW405833 in the transduced rat striatum. The hCB(2) expressions were followed for 9 months, which demonstrates the potential future clinical use of CB(2) as a PET reporter in the intact brain [69]. In another study [51], the PKM2 reporter gene was delivered to the brains of mice by adeno-associated virus (AAV9) via stereotactic injection. PET imaging at 8 weeks post AAV delivery showed that the AAV-injected mice had increases in [18F]DASA-23 brain uptake in the transduced sites. PKM2 can be used in the central nervous system to monitor gene and cell therapy without breaking the BBB.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23158443

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