Dataset Information

Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo 19F-Magnetic Resonance Spectroscopic Imaging.

ABSTRACT: Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.

SUBMITTER: Huber VJ

PROVIDER: S-EPMC6339703 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo <sup>19</sup>F-Magnetic Resonance Spectroscopic Imaging.

Huber Vincent J VJ Igarashi Hironaka H Ueki Satoshi S Terumitsu-Tsujita Mika M Nito Chikako C Ohno Ken K Suzuki Yuji Y Itoh Kosuke K Kwee Ingrid L IL Nakada Tsutomu T

Contrast media & molecular imaging 20190106

Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new <sup>19</sup>F-molecular ligand, TGF-019, for visualizing the distribution ...[more]

PMID: 30723388

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Project description:UnlabelledBackgroundNon-invasive imaging of inflammation to measure the progression of autoimmune diseases, such as rheumatoid arthritis (RA), and to monitor responses to therapy is critically needed. V-Sense, a perfluorocarbon (PFC) contrast agent that preferentially labels inflammatory cells, which are then recruited out of systemic circulation to sites of inflammation, enables detection by 19F MRI. With no 19F background in the host, detection is highly-specific and can act as a proxy biomarker of the degree of inflammation present.MethodsCollagen-induced arthritis in rats, a model with many similarities to human RA, was used to study the ability of the PFC contrast agent to reveal the accumulation of inflammation over time using 19F MRI. Disease progression in the rat hind limbs was monitored by caliper measurements and 19F MRI on days 15, 22 and 29, including the height of clinically symptomatic disease. Naïve rats served as controls. The capacity of the PFC contrast agent and 19F MRI to assess the effectiveness of therapy was studied in a cohort of rats administered oral prednisolone on days 14 to 28.ResultsQuantification of 19F signal measured by MRI in affected limbs was linearly correlated with disease severity. In animals with progressive disease, increases in 19F signal reflected the ongoing recruitment of inflammatory cells to the site, while no increase in 19F signal was observed in animals receiving treatment which resulted in clinical resolution of disease.ConclusionThese results indicate that 19F MRI may be used to quantitatively and qualitatively evaluate longitudinal responses to a therapeutic regimen, while additionally revealing the recruitment of monocytic cells involved in the inflammatory process to the anatomical site. This study may support the use of 19F MRI to clinically quantify and monitor the severity of inflammation, and to assess the effectiveness of treatments in RA and other diseases with an inflammatory component.

Project description:BackgroundMagnetic resonance imaging (MRI) is a promising tool for monitoring stem cell-based therapy. Conventionally, cells loaded with ironoxide nanoparticles appear hypointense on MR images. However, the contrast generated by ironoxide labeled cells is neither specific due to ambiguous background nor quantitative. A strategy to overcome these drawbacks is (19)F MRI of cells labeled with perfluorocarbons. We show here for the first time that human neural stem cells (NSCs), a promising candidate for clinical translation of stem cell-based therapy of the brain, can be labeled with (19)F as well as detected and quantified in vitro and after brain implantation.Methodology/principal findingsHuman NSCs were labeled with perfluoropolyether (PFPE). Labeling efficacy was assessed with (19)F MR spectroscopy, influence of the label on cell phenotypes studied by immunocytochemistry. For in vitro MRI, NSCs were suspended in gelatin at varying densities. For in vivo experiments, labeled NSCs were implanted into the striatum of mice. A decrease of cell viability was observed directly after incubation with PFPE, which re-normalized after 7 days in culture of the replated cells. No label-related changes in the numbers of Ki67, nestin, GFAP, or ?III-tubulin+ cells were detected, both in vitro and on histological sections. We found that 1,000 NSCs were needed to accumulate in one image voxel to generate significant signal-to-noise ratio in vitro. A detection limit of ?10,000 cells was found in vivo. The location and density of human cells (hunu+) on histological sections correlated well with observations in the (19)F MR images.Conclusion/significanceOur results show that NSCs can be efficiently labeled with (19)F with little effects on viability or proliferation and differentiation capacity. We show for the first time that (19)F MRI can be utilized for tracking human NSCs in brain implantation studies, which ultimately aim for restoring loss of function after acute and neurodegenerative disorders.

Dataset Information

Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo 19F-Magnetic Resonance Spectroscopic Imaging.

Publications

Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo <sup>19</sup>F-Magnetic Resonance Spectroscopic Imaging.

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