Correlated magnetic resonance imaging and ultramicroscopy (MR-UM) is a tool kit to assess the dynamics of glioma angiogenesis

Breckwoldt, Michael O.; Bode, Julia; Kurz, Felix T.; Hoffmann, Angelika; Ochs, Katharina; Ott, Martina; Deumelandt, Katrin; Krüwel, Thomas; Schwarz, Dániel; Fischer, Manuel; Helluy, Xavier; Milford, David V.; Kirschbaum, Klara; Solecki, Gergely; Chiblak, Sara; Abdollahi, Amir; Winkler, Frank; Wick, Wolfgang; Platten, Michael; Heiland, Sabine; Bendszus, Martin; Tews, Björn

doi:10.7554/elife.11712

Cited by 33 publications

(29 citation statements)

References 36 publications

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“…Afterwards, samples were stored at 4 °C and were imaged directly after clearing. Repetitive measurements were possible due to this fluorescence-conserving clearing method 15 33 .…”

Section: Methodsmentioning

confidence: 99%

Ultramicroscopy as a novel tool to unravel the tropism of AAV gene therapy vectors in the brain

Alves

Bode

Bemelmans

et al. 2016

Sci Rep

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Recombinant adeno-associated viral (AAV) vectors have advanced to the vanguard of gene therapy. Numerous naturally occurring serotypes have been used to target cells in various tissues. There is a strong need for fast and dynamic methods which efficiently unravel viral tropism in whole organs. Ultramicroscopy (UM) is a novel fluorescence microscopy technique that images optically cleared undissected specimens, achieving good resolutions at high penetration depths while being non-destructive. UM was applied to obtain high-resolution 3D analysis of AAV transduction in adult mouse brains, especially in the hippocampus, a region of interest for Alzheimer’s disease therapy. We separately or simultaneously compared transduction efficacies for commonly used serotypes (AAV9 and AAVrh10) using fluorescent reporter expression. We provide a detailed comparative and quantitative analysis of the transduction profiles. UM allowed a rapid analysis of marker fluorescence expression in neurons with intact projections deep inside the brain, in defined anatomical structures. Major hippocampal neuronal transduction was observed with both vectors, with slightly better efficacy for AAV9 in UM. Glial response and synaptic marker expression did not change post transduction.We propose UM as a novel valuable complementary tool to efficiently and simultaneously unravel tropism of different viruses in a single non-dissected adult rodent brain.

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“…Afterwards, samples were stored at 4 °C and were imaged directly after clearing. Repetitive measurements were possible due to this fluorescence-conserving clearing method 15 33 .…”

Section: Methodsmentioning

confidence: 99%

Ultramicroscopy as a novel tool to unravel the tropism of AAV gene therapy vectors in the brain

Alves

Bode

Bemelmans

et al. 2016

Sci Rep

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“…Clearing of Mouse Brains and Acquisition of UM Data. For UM analysis whole brains were optically cleared using the FluorClearBABB protocol (22,23). Additional details are given in SI Materials and Methods.…”

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confidence: 99%

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis

Kirschbaum

Sonner

Zeller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P < 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P < 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.MRI | nanoparticle imaging | USPIO | multiple sclerosis | EAE

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“…a and b ). Using a recently established ultramicroscopy platform (Fig. c ), we studied tumor invasion on the single‐cell level.…”

Section: Resultsmentioning

confidence: 99%

“…After clearing, the samples were stored at 4°C. The cleared brains were imaged using an UltraMicroscope II (LaVision BioTec, Bielefeld, Germany), as described previously . The detailed method is provided in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

A PRDX1‐p38α heterodimer amplifies MET‐driven invasion of IDH‐wildtype and IDH‐mutant gliomas

Wirthschaft

Bode

Simon

et al. 2018

Intl Journal of Cancer

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The Peroxiredoxin 1 (PRDX1) gene maps to chromosome arm 1p and is hemizygously deleted and epigenetically silenced in isocitrate dehydrogenase 1 or 2 (IDH)-mutant and 1p/19q-codeleted oligodendroglial tumors. In contrast, IDH-wildtype astrocytic gliomas including glioblastomas mostly lack epigenetic silencing and express PRDX1 protein. In our study, we investigated how PRDX1 contributes to the infiltrative growth of IDH-wildtype gliomas. Focusing on p38α-dependent pathways, we analyzed clinical data from 133 patients of the NOA-04 trial cohort to look for differences in the gene expression profiles of gliomas with wildtype or mutant IDH. Biochemical interaction studies as well as in vitro and ex vivo migration studies were used to establish a biological role of PRDX1 in maintaining pathway activity. Whole-brain high-resolution ultramicroscopy and survival analyses of pre-clinical mouse models for IDH-wildtype gliomas were then used for in vivo confirmation. Based on clinical data, we found that the absence of PRDX1 is associated with changes in the expression of MET/HGF signaling components. PRDX1 forms a heterodimer with p38α mitogen-activated protein kinase 14 (MAPK14), stabilizing phospho-p38α in glioma cells. This process amplifies hepatocyte growth factor (HGF)-mediated signaling and stimulates actin cytoskeleton dynamics that promote glioma cell migration. Whole-brain high-resolution ultramicroscopy confirms these findings, indicating that PRDX1 promotes glioma brain invasion in vivo. Finally, reduced expression of PRDX1 increased survival in mouse glioma models. Thus, our preclinical findings suggest that PRDX1 expression levels may serve as a molecular marker for patients who could benefit from targeted inhibition of MET/HGF signaling.

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Correlated magnetic resonance imaging and ultramicroscopy (MR-UM) is a tool kit to assess the dynamics of glioma angiogenesis

Cited by 33 publications

References 36 publications

Ultramicroscopy as a novel tool to unravel the tropism of AAV gene therapy vectors in the brain

Ultramicroscopy as a novel tool to unravel the tropism of AAV gene therapy vectors in the brain

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis

A PRDX1‐p38α heterodimer amplifies MET‐driven invasion of IDH‐wildtype and IDH‐mutant gliomas

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