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1. Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke

Author

Chloé Dumot, Chrystelle Po, Lucille Capin, Violaine Hubert, Elodie Ong, Matthieu Chourrout, Radu Bolbos, Camille Amaz, Céline Auxenfans, Emmanuelle Canet-Soulas, Claire Rome, Fabien Chauveau, and Marlène Wiart

Subjects
Medicine, Science
Abstract

Abstract With the aim of designing a preclinical study evaluating an intracerebral cell-based therapy for stroke, an observational study was performed in the rat suture model of ischemic stroke. Objectives were threefold: (i) to characterize neurofunctional and imaging readouts in the first weeks following transient ischemic stroke, according to lesion subtype (hypothalamic, striatal, corticostriatal); (ii) to confirm that intracerebral administration does not negatively impact these readouts; and (iii) to calculate sample sizes for a future therapeutic trial using these readouts as endpoints. Our results suggested that the most relevant endpoints were side bias (staircase test) and axial diffusivity (AD) (diffusion tensor imaging). Hypothalamic-only lesions did not affect those parameters, which were close to normal. Side bias in striatal lesions reached near-normal levels within 2 weeks, while rats with corticostriatal lesions remained impaired until week 14. AD values were decreased at 4 days and increased at 5 weeks post-surgery, with a subtype gradient: hypothalamic

Published
2022
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3. Disruption of Sema3A/Plexin‐A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination

Author

Fabien Binamé, Lucas D Pham‐Van, Caroline Spenlé, Valérie Jolivel, Dafni Birmpili, Lionel A Meyer, Laurent Jacob, Laurence Meyer, Ayikoé G Mensah‐Nyagan, Chrystelle Po, Michaël Van der Heyden, Guy Roussel, and Dominique Bagnard

Subjects
multiple sclerosis, myelination, oligodendrocyte, Plexin, Semaphorin, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Current treatments in multiple sclerosis (MS) are modulating the inflammatory component of the disease, but no drugs are currently available to repair lesions. Our study identifies in MS patients the overexpression of Plexin‐A1, the signalling receptor of the oligodendrocyte inhibitor Semaphorin 3A. Using a novel type of peptidic antagonist, we showed the possibility to counteract the Sema3A inhibitory effect on oligodendrocyte migration and differentiation in vitro when antagonizing Plexin‐A1. The use of this compound in vivo demonstrated a myelin protective effect as shown with DTI‐MRI and confirmed at the histological level in the mouse cuprizone model of induced demyelination/remyelination. This effect correlated with locomotor performances fully preserved in chronically treated animals. The administration of the peptide also showed protective effects, leading to a reduced severity of demyelination in the context of experimental autoimmune encephalitis (EAE). Hence, the disruption of the inhibitory microenvironmental molecular barriers allows normal myelinating cells to exert their spontaneous remyelinating capacity. This opens unprecedented therapeutic opportunity for patients suffering a disease for which no curative options are yet available.

Published
2019
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6. Ts66Yah, an upgraded Ts65Dn mouse model for Down syndrome, for only the region homologous to Human chromosome 21

Author

Arnaud Duchon, Maria del Mar Muñiz Moreno, Claire Chevalier, Valérie Nalesso, Philippe Andre, Marta Fructuoso-Castellar, Mary Mondino, Chrystelle Po, Vincent Noblet, Marie-Christine Birling, Marie-Claude Potier, and Yann Herault

Abstract

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with theMir155 toZbtb21region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8toPde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between theMir155-Zbtb21and theScaf8-Pde10ainterval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.

Published
2022
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7. Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke

Author

Camille Amaz, Marlène Wiart, Chrystelle Po, Claire Rome, Matthieu Chourrout, Chloé Dumot, Céline Auxenfans, Radu Bolbos, Elodie Ong, Emmanuelle Canet-Soulas, Fabien Chauveau, Violaine Hubert, Lucille Capin, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-18-CE19-0003,BREAKTHRU,Développement de l'imagerie bicolore à l'aide d'un scanner X spectral à comptage de photons pour l'évaluation in-vivo de thérapies cellulaires(2018), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Wiart, Marlene, and APPEL À PROJETS GÉNÉRIQUE 2018 - Développement de l'imagerie bicolore à l'aide d'un scanner X spectral à comptage de photons pour l'évaluation in-vivo de thérapies cellulaires - - BREAKTHRU2018 - ANR-18-CE19-0003 - AAPG2018 - VALID

Subjects
[SDV.IB] Life Sciences [q-bio]/Bioengineering, Multidisciplinary, business.industry, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, medicine.medical_treatment, Cell- and Tissue-Based Therapy, Stem-cell therapy, medicine.disease, Rats, 3. Good health, Stroke, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Neuroimaging, nervous system, medicine, Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Neuroscience, Ischemic Stroke
Abstract

With the aim of designing a preclinical study evaluating an intracerebral cell-based therapy for stroke, an observational study was performed in the rat suture model of ischemic stroke. Objectives were threefold: (i) to characterize neurofunctional and imaging readouts in the first weeks following transient ischemic stroke, according to lesion subtype (hypothalamic, striatal, corticostriatal); (ii) to confirm that intracerebral administration does not negatively impact these readouts; and (iii) to calculate sample sizes for a future therapeutic trial using these readouts as endpoints. Our results suggested that the most relevant endpoints were side bias (staircase test) and axial diffusivity (AD) (diffusion tensor imaging). Hypothalamic-only lesions did not affect those parameters, which were close to normal. Side bias in striatal lesions reached near-normal levels within 2 weeks, while rats with corticostriatal lesions remained impaired until week 14. AD values were decreased at 4 days and increased at 5 weeks post-surgery, with a subtype gradient: hypothalamic < striatal < corticostriatal. Intracerebral administration did not impact these readouts. After sample size calculation (18-147 rats per group according to the endpoint considered), we conclude that a therapeutic trial based on both readouts would be feasible only in the framework of a multicenter trial.

Published
2021
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8. Temporomandibular Joint Damage in K/BxN Arthritic Mice

Author

Sabine, Kuchler-Bopp, Alexandre, Mariotte, Marion, Strub, Chrystelle, Po, Aurore, De Cauwer, Georg, Schulz, Xavier, Van Bellinghen, Florence, Fioretti, François, Clauss, Philippe, Georgel, Nadia, Benkirane-Jessel, Fabien, Bornert, Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Immuno-Rhumatologie Moléculaire, Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Basel (Unibas), and univOAK, Archive ouverte

Subjects
musculoskeletal diseases, Temporomandibular Joint, Mice, Transgenic, X-Ray Microtomography, Arthritis, Experimental, Magnetic Resonance Imaging, Bone and Bones, Article, Arthritis, Rheumatoid, lcsh:RK1-715, Disease Models, Animal, Mice, Matrix Metalloproteinase 8, Animal disease models, lcsh:Dentistry, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rheumatoid arthritis, Tomography, X-Ray Computed
Abstract

Rheumatoid arthritis (RA) is an autoimmune disease affecting 1% of the world population and is characterized by chronic inflammation of the joints sometimes accompanied by extra-articular manifestations. K/BxN mice, originally described in 1996 as a model of polyarthritis, exhibit knee joint alterations. The aim of this study was to describe temporomandibular joint (TMJ) inflammation and damage in these mice. We used relevant imaging modalities, such as micro-magnetic resonance imaging (μMRI) and micro-computed tomography (μCT), as well as histology and immunofluorescence techniques to detect TMJ alterations in this mouse model. Histology and immunofluorescence for Col-I, Col-II, and aggrecan showed cartilage damage in the TMJ of K/BxN animals, which was also evidenced by μCT but was less pronounced than that seen in the knee joints. μMRI observations suggested an increased volume of the upper articular cavity, an indicator of an inflammatory process. Fibroblast-like synoviocytes (FLSs) isolated from the TMJ of K/BxN mice secreted inflammatory cytokines (IL-6 and IL-1β) and expressed degradative mediators such as matrix metalloproteinases (MMPs). K/BxN mice represent an attractive model for describing and investigating spontaneous damage to the TMJ, a painful disorder in humans with an etiology that is still poorly understood.

Published
2020
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9. NLRP3- and AIM2-autonomy in a mouse model of MSU crystal-induced acute inflammation in vivo suggests imiquimod-dependent targeting of Il-1[beta] expression as relevant therapy for gout patients

Author

Raphael Carapito, Benoît Frisch, Seiamak Bahram, Aurore DeCauwer, Ismael Aouadi, Nicodème Paul, Philippe Georgel, Alexandre Mariotte, Angélique Pichot, Cécile Macquin, Jean Sibilia, Emmanuel Chatelus, Chrystelle Po, Chérine Abou-Faycal, and Jean-Paul Armspach

Subjects
business.industry, Pattern recognition receptor, Inflammation, Inflammasome, Imiquimod, medicine.disease, Pathophysiology, Gout, AIM2, In vivo, medicine, Cancer research, medicine.symptom, business, medicine.drug
Abstract

The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1b in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1b; secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Here, we provide an extensive clinical, biological and molecular characterization of the acute uratic inflammation mouse model induced by subcutaneous injection of MSU crystals, which accurately mimics human gout. Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities, among which the use of topical application of imiquimod to promote interferon-dependent anti-inflammatory action maybe relevant.

Published
2019
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10. Improvement of the Off-Resonance Saturation, an MRI sequence for positive contrast with SPM particles: Theoretical and experimental study

Author

Quoc Lam Vuong, Bernard Gallez, Chrystelle Po, Sébastien Delangre, and Yves Gossuin

Subjects
Nuclear and High Energy Physics, Materials science, fungi, Biophysics, Specific absorption rate, 02 engineering and technology, Superparamagnetic nanoparticles, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Biochemistry, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Negative contrast, Nuclear magnetic resonance, Positive contrast, Off resonance, 0210 nano-technology, Saturation (magnetic), Superparamagnetism
Abstract

The SuperParaMagnetic particles (SPM particles) are used as contrast agents in MRI and produce negative contrast with conventional T2 or T2(∗)-weighted sequences. Unfortunately, the SPM particle detection on images acquired with such sequences is sometimes difficult because negative contrast can be created by artifacts such as air bubbles or calcification. To overcome this problem, new sequences as Off-Resonance Saturation (ORS) were developed to produce positive contrast with SPM particles. This work explores a new way to optimize the contrast generated by the ORS sequence by increasing the number of saturation pulses applied before the imaging sequence. This modified sequence is studied with numerical simulations and experiments on agarose gel phantoms. A theoretical model able to predict the contrast for different values of the sequence parameters is also developed. The results show that the contrast increases with the saturation pulses number with an optimal value of three saturation pulses in order to avoid artifacts and limit the Specific Absorption Rate (SAR) effect. The dependence of the contrast on the SPM particle concentration and sequence parameters is comparable to what was observed for the ORS sequence.

Published
2016
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11. From systemic inflammation to neuroinflammation: the case of neurolupus

Author

Sylviane Muller, Chrystelle Po, Mykolas Bendorius, Hélène Jeltsch-David, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), UMR 7242, Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Jeltsch-David, Hélène

Subjects
0301 basic medicine, Systemic disease, magnetic resonance imaging (MRI), medicine.medical_treatment, Aucun, Review, medicine.disease_cause, Systemic inflammation, blood–brain barrier, Autoimmunity, murine model, lcsh:Chemistry, 0302 clinical medicine, Lupus Erythematosus, Systemic, Sciences du Vivant [q-bio]/Immunologie, lcsh:QH301-705.5, Spectroscopy, systemic lupus erythematosus (SLE), Lupus Vasculitis, Central Nervous System, autoimmunity, General Medicine, Magnetic Resonance Imaging, 3. Good health, Computer Science Applications, medicine.anatomical_structure, Cytokine, Blood-Brain Barrier, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Central nervous system, Blood–brain barrier, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Immune system, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Physical and Theoretical Chemistry, Molecular Biology, Neuroinflammation, Inflammation, business.industry, behavior, Organic Chemistry, medicine.disease, neuropsychiatric lupus (NPSLE), 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Immunology, business, 030217 neurology & neurosurgery
Abstract

International audience; It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood⁻brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques.

Published
2018
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12. Bottom-up study of the MRI positive contrast created by the Off-Resonance Saturation sequence

Author

Sébastien Delangre, Daniel Henrard, Bernard Gallez, Quoc Lam Vuong, Chrystelle Po, and Yves Gossuin

Subjects
Saturation pulse, Nuclear and High Energy Physics, Scanner, Materials science, Biophysics, Metal Nanoparticles, Ferric Compounds, Biochemistry, chemistry.chemical_compound, Nuclear magnetic resonance, Off resonance, Image Processing, Computer-Assisted, medicine, Computer Simulation, Saturation (magnetic), medicine.diagnostic_test, Echo-Planar Imaging, Phantoms, Imaging, Sepharose, fungi, Magnetic resonance imaging, Condensed Matter Physics, Ferrosoferric Oxide, Transverse plane, chemistry, Positive contrast, Algorithms, Iron oxide nanoparticles
Abstract

Superparamagnetic iron oxide nanoparticles (SPM particles) are used in MRI to highlight regions such as tumors through negative contrast. Unfortunately, sources as air bubbles or tissues interfaces also lead to negative contrast, which complicates the image interpretation. New MRI sequences creating positive contrast in the particle surrounding, such as the Off-Resonance Saturation sequence (ORS), have thus been developed. However, a theoretical study of the ORS sequence is still lacking, which hampers the optimization of this sequence. For this reason, this work provides a self-consistent analytical expression able to predict the dependence of the contrast on the sequence parameters and the SPM particles properties. This expression was validated by numerical simulations and experiments on agarose gel phantoms on a 11.7 T scanner system. It provides a fundamental understanding of the mechanisms leading to positive contrast, which could allow the improvement of the sequence for future in vivo applications. The influence of the SPM particle relaxivities, the SPM particle concentration, the echo time and the saturation pulse parameters on the contrast were investigated. The best contrast was achieved with SPM particles possessing the smallest transverse relaxivity, an optimal particle concentration and for low echo times.

Published
2015
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13. Chemically-defined camelid antibody bioconjugate for the magnetic resonance imaging of Alzheimer's disease

Author

Charles Duyckaerts, Christelle Ganneau, Fiona Grueninger, Clémence Dudeffant, Benoît Delatour, Pascal Lenormand, Marc Dhenain, Chrystelle Po, Matthias Vandesquille, Christian Czech, Sylvie Bay, Tengfei Li, Pierre Lafaye, Chimie des Biomolécules - Chemistry of Biomolecules, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), F. Hoffmann-La Roche [Basel], CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), We gratefully acknowledge financial support from the Institut Roche de Recherche et Médecine Translationnelle. This work was also supported by the program 'Investissements d'avenir' ANR-10-IAIHU-06, the Pompidou Foundation and the France Alzheimer Foundation that are acknowledged. This work was partly carried out on the HISTOMICS platform of the ICM and the MRI platform of CEA-MIRCen, and we thank all technical staff involved., We are grateful to F. Bonhomme for the MS analyses by direct infusion, to F. Groh for the Amino Acid Analysis, to H. Cahuzac for helping in the synthesis of VHH conjugates, and to A. Louie (UC Davis) for providing access to 1.4 Tesla spectrometer and for training and advice on relaxometric analyses., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Amyloid, amyloid deposits, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Immunology, Blood–brain barrier, 03 medical and health sciences, Antigen, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Report, medicine, Alzheimer's disease diagnosis, Immunology and Allergy, magnetic resonance imaging, single-domain antibody, Bioconjugation, medicine.diagnostic_test, Chemistry, Magnetic resonance imaging, site-specific conjugation, Small molecule, 3. Good health, 030104 developmental biology, Single-domain antibody, medicine.anatomical_structure, Biophysics, Molecular imaging, chemically-defined imaging probe
Abstract

International audience; Today, molecular imaging of neurodegenerative diseases is mainly based on small molecule probes. Alternatively, antibodies are versatile tools that may be developed as new imaging agents. Indeed, they can be readily obtained to specifically target any antigen of interest and their scaffold can be functionalized. One of the critical issues involved in translating antibody-based probes to the clinic is the design and synthesis of perfectly-defined conjugates. Camelid single-domain antibody-fragments (VHHs) are very small and stable antibodies that are able to diffuse in tissues and potentially cross the blood brain barrier (BBB). Here, we selected a VHH (R3VQ) specifically targeting one of the main lesions of Alzheimer's disease (AD), namely the amyloid-beta (Aß) deposits. It was used as a scaffold for the design of imaging probes for magnetic resonance imaging (MRI) and labeled with the contrastophore gadolinium using either a random or site-specific approach. In contrast to the random strategy, the site-specific conjugation to a single reduced cysteine in the C-terminal part of the R3VQ generates a well-defined bioconjugate in a high yield process. This new imaging probe is able to cross the BBB and label Aß deposits after intravenous injection. Also, it displays improved r1 and r2 relaxivities, up to 30 times higher than a widely used clinical contrast agent, and it allows MRI detection of amyloid deposits in post mortem brain tissue of a mouse model of AD. The ability to produce chemically-defined VHH conjugates that cross the BBB opens the way for future development of tailored imaging probes targeting intracerebral antigens.

Published
2017
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14. WD40-repeat 47 is essential for brain development via microtubule-mediated processes and autophagy

Author

Binnaz Yalcin, Meghna Kannan, Christel Wagner, Marna Roos, Bruno Rinaldi, Perrine Kretz, Lara Mcgillewie, Séverine Bär, Shilpi Minocha, Chrystelle Po, Jamel Chelly, Jean-Louis Mandel, Renato Borgatti, Amélie Piton, Stephan Collins, Craig Kinnear, Yann Herault, Sylvie Friant, Ben Loos, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), IRCCS Eugenio Medea, IRCCS, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Friant, Sylvie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Stellenbosch University, Université de Strasbourg (UNISTRA), Medical Research Council, Fédération de Médecine Translationelle de Strasbourg (FMTS), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Lausanne = University of Lausanne (UNIL), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

Erreur dates et n° de conférence dans l'url https://hal.archives-ouvertes.fr/hal-02378786.; International audience

Published
2017

15. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Author

David J. Adams, Jamel Chelly, Lara Mcgillewie, Christel Wagner, Ben Loos, Bruno Rinaldi, Sylvie Friant, Stephan C. Collins, Craig J. Kinnear, Perrine F. Kretz, Renato Borgatti, Yann Herault, Jean-Louis Mandel, Juliette D. Godin, Efil Bayam, Binnaz Yalcin, Chrystelle Po, Meghna Kannan, Marna Roos, Shilpi Minocha, Séverine Bär, Peggy Tilly, Claire Chevalier, Amélie Piton, Friant, Sylvie, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), IRCCS Eugenio Medea, IRCCS, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut Clinique de la Souris (ICS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), CNRS (S.F.), INSERM (E.B. and S.F.), Strasbourg University (S.F.), Initiatives d'Excellence (IDEX) 2015 Attractivite (S.B.), and Grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d'Avenir ANR-10-IDEX-0002-02 (to B.Y. and J.D.G.). C.K. is supported by funding from the South African Medical Research Council. B.Y. is supported by the Jerome Lejeune Foundation, the French National Research Agency (ANR-11-PDOC-0029), and the Gutenberg Circle., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Male, 0301 basic medicine, Microcephaly, autophagy, WD40 Repeats, Microtubule-associated protein, [SDV]Life Sciences [q-bio], Lissencephaly, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Microtubules, Mice, 03 medical and health sciences, 0302 clinical medicine, WD40 repeat, Cell Movement, medicine, Animals, microcephaly, Growth cone, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Neurons, Multidisciplinary, Corpus Callosum Agenesis, Stem Cells, WD40-repeat proteins, Microfilament Proteins, Neurogenesis, Brain, medicine.disease, Neural stem cell, Mice, Inbred C57BL, corpus callosum agenesis, [SDV] Life Sciences [q-bio], neurogenesis, Phenotype, 030104 developmental biology, PNAS Plus, Female, Microtubule-Associated Proteins, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1 , Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.

Published
2017
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16. The Blood Flow Shutdown Induced by Combretastatin A4 Impairs Gemcitabine Delivery in a Mouse Hepatocarcinoma

Author

Anne-Catherine Fruytier, Bernard Gallez, Julie Magat, Cécile S. Le Duff, Olivier Feron, Caroline Bouzin, Bénédicte F. Jordan, Chrystelle Po, Marie-Aline Neveu, UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, and UCL - SST/IMCN - Institute of Condensed Matter and Nanosciences

Subjects
0301 basic medicine, Tumor perfusion, DCE-MRI, Shutdown, medicine.medical_treatment, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Vascular disrupting agent, tumor perfusion, medicine, Distribution (pharmacology), 19F NMR, Pharmacology (medical), Active metabolite, Original Research, Chemotherapy, business.industry, Blood flow, Gemcitabine, 030104 developmental biology, 030220 oncology & carcinogenesis, Drug delivery, drug delivery, vascular disrupting agent, business, Ex vivo, medicine.drug
Abstract

In recent clinical studies, vascular disrupting agents (VDAs) are mainly used in combination with chemotherapy. However, an often overlooked concern in treatment combination is the VDA-induced impairment of chemotherapy distribution in the tumor. The work presented here investigated the impact of blood flow shutdown induced by Combretastatin A4 (CA4) on gemcitabine uptake into mouse hepatocarcinoma. At 2 hours after CA4 treatment, using DCE-MRI, a significant decrease in the perfusion-relevant parameters Ktrans and Vp were observed in treated group compared with the control group. The blood flow shutdown was indeed confirmed by a histology study. In a third experiment, the total gemcitabine uptake was found to be significantly lower in treated tumors, as assessed in a separate experiment using ex vivo fluorine nuclear magnetic resonance spectroscopy. The amount of active metabolite gemcitabine triphosphate was also lower in treated tumors. In conclusion, the blood flow shutdown induced by VDAs can impact negatively on the delivery of small cytotoxic agents in tumors. The present study outlines the importance of monitoring the tumor vascular function when designing drug combinations.

Published
2016
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17. Erratum to: High field magnetic resonance imaging of rodents in cardiovascular research

Author

Olivier Feron, Jean-Luc Balligand, Bernhard Gerber, Bernard Gallez, Chrystelle Po, Laetitia Vanhoutte, Julie Magat, and Stéphane Moniotte

Subjects
Physics, Nuclear magnetic resonance, High field magnetic resonance imaging, Physiology, Physiology (medical), Cardiovascular research, Cardiology and Cardiovascular Medicine
Abstract

The online version of the original article can be found under doi: 10.1007/s00395-016-0565-2 .

Published
2016
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18. Four Gadolinium(III) Complexes Appended to a Porphyrin: A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the Photosensitizer

Author

Célia S. Bonnet, Barbara Ventura, Paulo Loureiro de Sousa, Angélique Sour, Valérie Heitz, Ana Ortí-Suárez, Sébastien Jenni, Éva Tóth, Chrystelle Po, Agnès Pallier, Julie Schmitt, Frédéric Bolze, Université de Strasbourg (UNISTRA), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Physique Biologique, Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Istituto per la Sintesi Organica e la Fotoreattività (ISOF-CNR), Consiglio Nazionale delle Ricerche (CNR), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Porphyrins, Light, MRI contrast agent, medicine.medical_treatment, Gadolinium, Proton Magnetic Resonance Spectroscopy, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Photodynamic therapy, 010402 general chemistry, 01 natural sciences, Theranostic Nanomedicine, Inorganic Chemistry, chemistry.chemical_compound, Nuclear magnetic resonance, Coordination Complexes, medicine, Humans, Photosensitizer, Yttrium, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Physical and Theoretical Chemistry, ComputingMilieux_MISCELLANEOUS, Photosensitizing Agents, Cell Death, 010405 organic chemistry, Singlet oxygen, HIGH MAGNETIC-FIELD, CONTRAST AGENTS, PHOTODYNAMIC THERAPY, CANCER-THERAPY, DRUG-DELIVERY, BRAIN-TUMORS, NANOPARTICLES, RESONANCE, NANOMEDICINE, DESIGN, Water, Porphyrin, Magnetic Resonance Imaging, 0104 chemical sciences, chemistry, Solubility, Chimie/Chimie inorganique, Phototoxicity, Lysosomes, Conjugate, HeLa Cells
Abstract

A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA](-) complexes (DTTA(4-) = diethylenetriamine-N,N,N",N"-tetraacetate) linked to a meso-tetraphenylporphyrin core, as well as its yttrium(III) analogue, was synthesized. A variety of physicochemical methods were used to characterize the gadolinium(III) conjugate 1 both as an MRI contrast agent and as a photosensitizer. The proton relaxivity measured in H2O at 20 MHz and 25 degrees C, r(1) = 43.7 mmol(-1) s(-1) per gadolinium center, is the highest reported for a bishydrated gadolinium(III)-based contrast agent of medium size and can be related to the rigidity of the molecule. The complex displays also a remarkable singlet oxygen quantum yield of phi(Delta) = 0.45 in H2O, similar to that of a meso-tetrasulfonated porphyrin. We also evidenced the ability of the gadolinium(III) conjugate to penetrate in cancer cells with low cytotoxicity. Its phototoxicity on Hela cells was evaluated following incubation at low micromolar concentration and moderate light irradiation (21 J cm(-2)) induced 50% of cell death. Altogether, these results demonstrate the high potential of this conjugate as a theranostic agent for MRI and PDT.

Published
2016
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19. High field magnetic resonance imaging of rodents in cardiovascular research

Author

Bernard Gallez, Julie Magat, Olivier Feron, Bernhard Gerber, Stéphane Moniotte, Laetitia Vanhoutte, Chrystelle Po, and Jean-Luc Balligand

Subjects
Pathology, medicine.medical_specialty, High field magnetic resonance imaging, Physiology, Cardiac anatomy, Cardiovascular research, 030204 cardiovascular system & hematology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Mice, 0302 clinical medicine, Physiology (medical), medicine, Animals, Humans, High field strength, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Heart, Gold standard (test), Magnetic Resonance Imaging, Disease Models, Animal, Cardiovascular Diseases, High field, Cardiology and Cardiovascular Medicine, business, Neuroscience
Abstract

Transgenic and gene knockout rodent models are primordial to study pathophysiological processes in cardiovascular research. Over time, cardiac MRI has become a gold standard for in vivo evaluation of such models. Technical advances have led to the development of magnets with increasingly high field strength, allowing specific investigation of cardiac anatomy, global and regional function, viability, perfusion or vascular parameters. The aim of this report is to provide a review of the various sequences and techniques available to image mice on 7-11.7 T magnets and relevant to the clinical setting in humans. Specific technical aspects due to the rise of the magnetic field are also discussed.

Published
2015

20. Vascular change and opposing effects of the angiotensin type 2 receptor in a mouse model of vascular cognitive impairment

Author

Martina Füchtemeier, Caterina Curato, Chrystelle Po, Marie P Brinckmann, Alexander Kunz, Tracy D. Farr, Marco Foddis, and Ulrich Dirnagl

Subjects
Male, Pathology, Angiotensin II Type 2 Receptor Blockers, metabolism [Receptor, Angiotensin, Type 2], Mice, drug effects [Cerebrovascular Circulation], pathology [Brain], mouse hypoperfusion, Image Processing, Computer-Assisted, education.field_of_study, medicine.diagnostic_test, Brain, metabolism [Dementia, Vascular], diffusion tensor imaging, Flow Cytometry, Magnetic Resonance Imaging, Neurology, Cerebral blood flow, Cerebrovascular Circulation, Original Article, drug effects [Brain], pharmacology [Angiotensin II Type 2 Receptor Blockers], Cardiology and Cardiovascular Medicine, Perfusion, medicine.medical_specialty, physiology [Cerebrovascular Circulation], Receptor, Angiotensin, Type 2, Vascular remodelling in the embryo, angiotensin II receptor type 2, medicine.artery, medicine, Basilar artery, Animals, ddc:610, Cerebral perfusion pressure, education, pathology [Dementia, Vascular], vascular cognitive impairment, business.industry, Dementia, Vascular, Magnetic resonance imaging, Angiotensin II receptor type 2, Mice, Inbred C57BL, perfusion weighted imaging, Disease Models, Animal, metabolism [Brain], Neurology (clinical), business, Neuroscience, Circle of Willis
Abstract

Our aims were to assess the spatiotemporal development of brain pathology in a mouse model of chronic hypoperfusion using magnetic resonance imaging (MRI), and to test whether the renin-angiotensin system (RAS) can offer therapeutic benefit. For the first time, different patterns of cerebral blood flow alterations were observed in hypoperfused mice that ranged from an immediate and dramatic to a delayed decrease in cerebral perfusion. Diffusion tensor imaging revealed increases in several quantitative parameters in different brain regions that are indicative of white-matter degeneration; this began around 3 weeks after induction of hypoperfusion. While this model may be more variable than previously reported, neuroimaging tools represent a promising way to identify surrogate markers of pathology. Vascular remodelling was observed in hypoperfused mice, particularly in the anterior part of the Circle of Willis. While the angiotensin II receptor type 2 agonist, Compound 21 (C21), did not influence this response, it did promote expansion of the basilar artery in microcoil animals. Furthermore, C21-treated animals exhibited increased brain lymphocyte infiltration, and importantly, C21 had opposing effects on spatial reference memory in hypoperfused and sham mice. These results suggest that the RAS may have a role in vascular cognitive impairment.

Published
2015
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