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2. Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function

Author

Ramin-Mangata, Stéphane, Thedrez, Aurélie, Nativel, Brice, Diotel, Nicolas, Blanchard, Valentin, Wargny, Matthieu, Aguesse, Audrey, Billon-Crossouard, Stéphanie, Vindis, Cécile, Le May, Cédric, Hulin, Philippe, Armanet, Mathieu, Gmyr, Valery, Pattou, François, Croyal, Mikaël, Meilhac, Olivier, Nobécourt, Estelle, Cariou, Bertrand, and Lambert, Gilles

Published
2021
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5. Neuropathologic, phenotypic and functional analyses of Mucosal Associated Invariant T cells in Multiple Sclerosis

Author

Salou, Marion, Nicol, Bryan, Garcia, Alexandra, Baron, Daniel, Michel, Laure, Elong-Ngono, Annie, Hulin, Philippe, Nedellec, Steven, Jacq-Foucher, Marylène, Le Frère, Fabienne, Jousset, Natacha, Bourreille, Arnaud, Wiertlewski, Sandrine, Soulillou, Jean-Paul, Brouard, Sophie, Nicot, Arnaud B., Degauque, Nicolas, and Laplaud, David-Axel

Published
2016
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6. The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition

Author

Decombis, Salomé, Papin, Antonin, Bellanger, Céline, Sortais, Clara, Dousset, Christelle, Le Bris, Yannick, Riveron, Thiphanie, Blandin, Stéphanie, Hulin, Philippe, Tessoulin, Benoit, Rouel, Mathieu, Le Gouill, Steven, Moreau-Aubry, Agnès, Pellat-Deceunynck, Catherine, Chiron, David, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), L’Héma-NexT [UNIV Nantes] (i-Site NexT), Université de Nantes (UN), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Biologique [CHU Nantes], Plate-forme de 'transgénèse immunophénomique du rat' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), and Chiron, David

Subjects
immune system diseases, hemic and lymphatic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Hematology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
Abstract

International audience; Aggressive B-cell malignancies, such as mantle cell lymphoma (MCL), are microenvironment-dependent tumors and a better understanding of the dialogs occurring in lymphoma protective ecosystems will provide new perspectives to increase treatment efficiency. To identify novel molecular regulations, we performed a transcriptomic analysis based on the comparison of circulating (n=77) versus MCL lymph nodes (n=107) together with RNA sequencing of malignant (n=8) versus normal B-cell (n=6) samples. This integrated analysis led to the discovery of microenvironment-dependent and tumor-specific secretion of the interleukin-32 beta (IL32β), whose expression was confirmed in situ within MCL lymph nodes by multiplex immunohistochemistry. Using ex vivo models of primary MCL cells (n=23), we demonstrated that, through the secretion of IL32β, the tumor was able to polarize monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFNB inhibition to counteract microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. This data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophages polarization and tumor survival, which could be counteracted through selective NIK inhibition.

Published
2022

11. Impact of RAFT Chain Transfer Agents on the Polymeric Shell Density of Magneto-Fluorescent Nanoparticles and Their Cellular Uptake

Author

Blondy, Thibaut, primary, Poly, Julien, additional, Linot, Camille, additional, Boucard, Joanna, additional, Allard-Vannier, Emilie, additional, Nedellec, Steven, additional, Hulin, Philippe, additional, Henoumont, Céline, additional, Larbanoix, Lionel, additional, Muller, Robert N, additional, Laurent, Sophie, additional, Ishow, Eléna, additional, and Blanquart, Christophe, additional

Published
2022
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12. Short OGA (O-GlcNAcase) is targeted to the mitochondria and regulates mitochondrial reactive oxygen species level

Author

Pagesy, Patrick, Bouaboud, Abdelouhab, Feng, Zhihao, Hulin, Philippe, Issad, Tarik, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre hospitalier universitaire de Nantes (CHU Nantes), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
[SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Abstract

O-GlcNAcylation is a reversible post-translational modification involved the regulation of cytosolic, nuclear and mitochondrial proteins. Only two enzymes, OGT and OGA, control attachment and removal of O-GlcNAc on proteins, respectively. Whereas a variant OGT (mOGT) has been proposed as the main isoform that O-GlcNAcylates proteins in mitochondria, identification of a mitochondrial OGA has not been performed yet. Two splice variants of OGA (short and long isoforms) have been described previously. In this work, using cell fractionation experiments, we show that short-OGA is preferentially recovered in mitochondria-enriched fractions from HEK-293T cells as well as mouse embryonic fibroblasts. Moreover, fluorescent microscopy imaging confirmed that GFP-tagged short-OGA is addressed to mitochondria. In addition, using a BRET-based mitochondrial O-GlcNAcylation biosensor, we show that co-transfection of short-OGA markedly reduced O-GlcNAcylation of the biosensor, whereas long-OGA had no significant effect. Finally, using genetically encoded or chemical fluorescent mitochondrial probes, we showed that short-OGA overexpression increases mitochondrial ROS levels, whereas long-OGA had no significant effect. Together, our work reveals that the short-OGA isoform is targeted to the mitochondria where it regulates ROS homoeostasis.

Published
2021

13. The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons

Author

Bodin, Raphael, Paillé, Vincent, Oullier, Thibauld, Durand, Tony, Aubert, Philippe, Le Berre-Scoul, Catherine, Hulin, Philippe, Neunlist, Michel, Cissé, Moustapha, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Plateforme MicroPicell [Nantes], and Université de Nantes (UN)

Subjects
DMEM, Dulbecco's modified Eagle medium, MAP Kinase Signaling System, Receptor, EphB2, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], synapsin I, enteric neurons, CNS, central nervous system, Rats, Sprague-Dawley, EGC, enteric glial cell, enteric nervous system, FBS, fetal bovine serum, synaptic-associated proteins, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neurons, ENS, enteric nervous system, Neuronal Plasticity, ephrinB2, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SCCO.NEUR]Cognitive science/Neuroscience, SAP, synaptic-associated protein, PSD95, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, EphB2, Rats, OD, optical density, enteric glial cells, nervous system, connectivity, Synapses, Fc, fragment crystalizable, mPSC, miniature postsynaptic current, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

International audience; Highly organized circuits of enteric neurons are required for the regulation of gastrointestinal functions, such as peristaltism or migrating motor complex. However, the factors and molecular mechanisms that regulate the connectivity of enteric neurons and their assembly into functional neuronal networks are largely unknown. A better understanding of the mechanisms by which neurotrophic factors regulate this enteric neuron circuitry is paramount to understanding enteric nervous system (ENS) physiology. EphB2, a receptor tyrosine kinase, is essential for neuronal connectivity and plasticity in the brain, but so far its presence and function in the ENS remain largely unexplored. Here we report that EphB2 is expressed preferentially by enteric neurons relative to glial cells throughout the gut in rats. We show that in primary enteric neurons, activation of EphB2 by its natural ligand ephrinB2 engages ERK signaling pathways. Long-term activation with ephrinB2 decreases EphB2 expression and reduces molecular and functional connectivity in enteric neurons without affecting neuronal density, ganglionic fiber bundles, or overall neuronal morphology. This is highlighted by a loss of neuronal plasticity markers such as synapsin I, PSD95, and synaptophysin, and a decrease of spontaneous miniature synaptic currents. Together, these data identify a critical role for EphB2 in the ENS and reveal a unique EphB2-mediated molecular program of synapse regulation in enteric neurons.

Published
2021

15. The IL32/BAFF Axis Supports Prosurvival Dialog in the Lymphoma Ecosystem and Is Disrupted By NIK Inhibition

Author

Decombis, Salome, primary, Papin, Antonin, additional, Bellanger, Celine, additional, Sortais, Clara, additional, Dousset, Christelle, additional, Le Bris, Yannick, additional, Blandin, Stephanie, additional, Hulin, Philippe, additional, Tessoulin, Benoit, additional, Rouel, Mathieu, additional, Le Gouill, Steven, additional, Moreau-Aubry, Agnes, additional, Pellat-Deceunynck, Catherine, additional, and Chiron, David, additional

Published
2021
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17. Imagerie tri-dimensionnelle d’échantillons par une technique de serial block face imaging amovible

Author

Malloci, Marine, Blandin, Stéphanie, Hulin, Philippe, Dorval, Paul, nedellec, steven, Schmid, Guillaume, Dancer, Pierre-Alix, Paul-Gilloteaux, Perrine, Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Kaerlabs, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and ANR-18-CE45-0015,CROCOVAL,Recalage transmodal en microscopies corrélatives pour la caractérisation physiopathologique de la valvulopathie(2018)

Subjects
[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Histologie, microscopie, analyse 3D, Serial Block Face Imaging, Histology, microscopy, 3D analysis, Serial Block Face Imaging, ComputingMilieux_MISCELLANEOUS
Abstract

L’analyse tridimensionnelle d’un échantillon par Serial Block Face Imaging trouve ses champs d’application dans l’étude de la micro-anatomie et la biologie du développement. Le concept est de produire une grande quantité d’images directement à partir de la surface d’un bloc dans lequel est inclus l’échantillon, et ce, au fur et à mesure de sa coupe (au microtome ou cryostat). Les images sériées sont de fait déjà pré-alignées et permettent de reconstruire en trois dimensions l’échantillon et de l’explorer selon n’importe quel plan de coupe virtuel. La plateforme MicroPICell et la société Kaer Labs collaborent afin de reproduire cette technique, avec une caméra amovible comprenant une source d’excitation LED intégrée, positionnée en face d’un microtome ou d’un cryostat classique. A partir d’organes soit inclus en paraffine colorée soit congelés et enrobés dans de l’OCT, cette technique nous a permis d’acquérir des images en série grâce au contraste de fluorescence entre l’échantillon et le milieu d’enrobage. Nous avons pu ensuite faire une reconstruction 3D de ces échantillons, en conservant leurs structures. Par rapport aux systèmes commerciaux disponibles, ce système est peu onéreux, demande une préparation simple des échantillons et est adaptable aussi bien pour des échantillons inclus en paraffine qu’en congelé., The three-dimensional analysis of sample by Serial Block Face Imaging finds its fields of application in the study of micro-anatomy and developmental biology. The concept is to produce a large amount of images directly from the surface of a block in which the sample is included, as it is cut (microtome or cryostat). Serial images are already pre-aligned and allow reconstructing the sample in three dimensions and exploring it in any virtual cutting plane. The MicroPICell platform and the company Kaer Labs are collaborating to develop this technique, by combining a removable camera with an integrated LED excitation source, positioned in front of a conventional microtome or cryostat. From organs included in colored paraffin or frozen in OCT, this technique allowed us to acquire serial images thanks to the fluorescence contrast between the sample and the embedding medium. We could then make a simplified 3D reconstruction of these samples, keeping their structures. Compared to the commercial systems available, this system is inexpensive, requires simple sample preparation and is adaptable for both paraffin and frozen samples.

Published
2020

18. Non-permissive human conventional CD1c+ dendritic cells enable trans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

Author

Sikorski, Mathieu, primary, Coulon, Flora, additional, Peltier, Cécile, additional, Braudeau, Cécile, additional, Garcia, Alexandra, additional, Giraud, Matthieu, additional, Renaudin, Karine, additional, Kandel-Aznar, Christine, additional, Nedellec, Steven, additional, Hulin, Philippe, additional, Branchereau, Julien, additional, Véziers, Joëlle, additional, Gaboriaud, Pauline, additional, Touzé, Antoine, additional, Burlaud-Gaillard, Julien, additional, Josien, Régis, additional, McIlroy, Dorian, additional, Bressollette-Bodin, Céline, additional, and Halary, Franck, additional

Published
2021
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21. Maurocalcin and its analog MCaE12A facilitate Ca2+ mobilization in cardiomyocytes

Author

De Waard, Stephan, primary, Montnach, Jérome, additional, Cortinovis, Charly, additional, Chkir, Olfa, additional, Erfanian, Morteza, additional, Hulin, Philippe, additional, Gaborit, Nathalie, additional, Lemarchand, Patricia, additional, Mesirca, Pietro, additional, Bidaud, Isabelle, additional, Mangoni, Matteo E., additional, De Waard, Michel, additional, and Ronjat, Michel, additional

Published
2020
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23. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter

Author

Prie, Dominique, Huart, Virginie, Bakouh, Naziha, Planelles, Gabrielle, Dellis, Olivier, Gerard, Benedicte, Hulin, Philippe, Benque-Blanchet, Francois, Silve, Caroline, Grandchamp, Bernard, and Friedlander, Gerard

Subjects
Kidney stones -- Genetic aspects, Osteoporosis -- Genetic aspects, Hypophosphatemia -- Genetic aspects
Abstract

A mutation in the gene for the sodium-phosphate cotransporter in the kidneys may increase a person's risk of developing kidney stones and osteoporosis. The mutation causes phosphate to be excreted in urine instead of being re-absorbed back into the blood. In a study of 20 patients with recurring kidney stones or osteoporosis who also had low blood phosphate levels, two had a mutation in the gene for the sodium-phosphate cotransporter.

Published
2002

24. Effect of reactive oxygen species on N[H.sup.+.sub.4] permeation in Xenopus laevis oocytes

Author

Cougnon, Marc, Benammou, Samia, Brouillard, Franck, Hulin, Philippe, and Planelles, Gabrielle

Subjects
Bioelectrochemistry -- Research, Membrane potentials -- Analysis, Ammonium -- Physiological aspects, Cellular control mechanisms -- Physiological aspects, Biological sciences
Abstract

To investigate the effects of reactive oxygen species (ROS) on N[H.sup.+.sub.4] permeation in Xenopus laevis oocytes, we used intracellular double-barreled microelectrodes to monitor the changes in membrane potential ([V.sub.m]) and intracellular pH (p[H.sub.i]) induced by a 20 mM N[H.sub.4]Cl-containing solution. Under control conditions, N[H.sub.4]Cl exposure induced a large membrane depolarization (to [V.sub.m] = 4.0 [+ or -] 1.5 mV; n = 21) and intracellular acidification [reaching a change in p[H.sub.i] ([DELTA]p[H.sub.i]) of 0.59 [+ or -] 0.06 pH units in 12 min]; the initial rate of cell acidification (dp[H.sub.i]/dt) was 0.06 [+ or -] 0.01 pH units/min. Incubation of the oocytes in the presence of [H.sub.2][O.sub.2] or [beta]-amyloid protein had no marked effect on the N[H.sub.4]Cl-induced [DELTA]p[H.sub.i]. By contrast, in the presence of photoactivated rose bengal (RB), tert-butyl-hydroxyperoxide (t-BHP), or xanthine/xanthine oxidase (X/XO), the same experimental maneuver induced significantly greater [DELTA]p[H.sub.i] and dp[H.sub.i]/dt. These increases in [DELTA]p[H.sub.i] and dp[H.sub.i]/dt were prevented by the ROS scavengers histidine and desferrioxamine, suggesting involvement of the reactive species [sup.1][DELTA]G[O.sub.2] and * OH. Using the voltage-clamp technique to identify the mechanism underlying the ROS-measured effects, we found that RB induced a large increase in the oocyte membrane conductance ([G.sub.m]). This RB-induced [G.sub.m] increase was prevented by 1 mM diphenylamine-2-carboxylate (DPC) and by a low [Na.sup.+] concentration in the bath. We conclude that RB, t-BHP, and X/XO enhance N[H.sup.+.sub.4] influx into the oocyte via activation of a DPC-sensitive nonselective cation conductance pathway. ammonium ions; nonselective cationic conductance

Published
2002

27. Analyse d’un échantillon en 3 dimensions par une technique de Serial Block Face Imaging amovible

Author

Malloci, Marine, Blandin, Stéphanie, Dorval, Paul, Hulin, Philippe, Dancer, Pierre-Alix, Paul-Gilloteaux, Perrine, Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), ANR-18-CE45-0015,CROCOVAL,Recalage transmodal en microscopies corrélatives pour la caractérisation physiopathologique de la valvulopathie(2018), Paul-Gilloteaux, Perrine, and APPEL À PROJETS GÉNÉRIQUE 2018 - Recalage transmodal en microscopies corrélatives pour la caractérisation physiopathologique de la valvulopathie - - CROCOVAL2018 - ANR-18-CE45-0015 - AAPG2018 - VALID

Subjects
[SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging
Abstract

International audience; L’analyse tridimensionnelle d’un échantillon trouve ses champs d’application dans l’étude de la micro anatomie et la biologie du développement Elle peut être réalisée à partir d’échantillons histologiques Le principe méthodique est de générer une grande quantité d’images directement à partir de la surface du bloc dans lequel est inclus l’échantillon, et ce, au fur et à mesure qu’il soit sectionné mécaniquement (technique de Serial Block Face Imaging) Les images sériées sont alors déjà alignées et permettent de reconstruire en trois dimensions l’échantillon, afin de l’explorer selon n’importe quel plan de coupe virtuel Actuellement, il existe sur le marché différents systèmes intégrés de microscopie épiscopique haute résolution ( mais les appareils et leurs consommables sont onéreux, la préparation des échantillons est fastidieuse et toxique (fixation en méthanol, inclusion en résine colorée JB 4 Polyscience Par rapport aux systèmes d'HREM commerciaux, cette technique demande une préparation plus simple et moins onéreuse des échantillons. De plus, ce système est modulable, peu encombrant et adaptable aussi bien pour des échantillons inclus en paraffine qu'en congelé. Cette technique nous a permis de faire une reconstruction simplifiée qui conserve les structures de l'échantillon. Les structures demeurent mieux conservées en paraffine qu'en congelé. En congelé, nous avons montré la possibilité de travailler avec des marquages fluorescents type GFP.  En perspectives, nous travaillons à automatiser ce système (prise d'images et coupe). Il sera également nécessaire de tester d'autres échantillons (cerveau, oeil…). En ajoutant une deuxième source laser en excitation (647 nm), cela nous permettrait de visualiser des marquages dans le rouge lointain pour les échantillons congelés, afin de les distinguer de l'autofluorescence du tissus. Enfin, nous travaillons à un système pour récupérer les coupes et faire des colorations et immunomarquages sur les zones d'intérêts.

Published
2019

29. Symmetric pH dependence of buffering power in giant fused cells from frog kidney proximal tubule

Author

Bouyer, Patrice, Cougnon, Marc, Thomas, Randall S., Hulin, Philippe, Anagnostopoulos, Takis, and Planelles, Gabrielle

Subjects
Hydrogen-ion concentration -- Physiological aspects, Kidney tubules -- Physiological aspects, Biological transport -- Physiological aspects, Biological sciences
Abstract

Intracellular hydrogen-ion concentration (pHi) and transmembrane potentials were monitored during acid or alkaline cell loading in frog kidney proximal tubule cells. Analysis of the intrinsic buffering power (beta1) of giant fused cells of Rana ridibunda indicated the relative importance of the beta1 of the CO2-bicarbonate pair during alkaline cell loading. Furthermore, frog proximal tubular cells restored their pHi after acid and alkaline cell loading via Na+- and bicarbonate-independent mechanisms.

Published
1997

34. Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death

Author

Iradyan, Melkon, primary, Iradyan, Nina, additional, Hulin, Philippe, additional, Hambardzumyan, Artur, additional, Gyulkhandanyan, Aram, additional, Alves de Sousa, Rodolphe, additional, Hessani, Assia, additional, Roussakis, Christos, additional, Bollot, Guillaume, additional, Bauvais, Cyril, additional, and Sakanyan, Vehary, additional

Published
2019
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36. Spatio-Temporal Analysis of Human Preimplantation Development Reveals Dynamics of Epiblast and Trophectoderm Specification

Author

Meistermann, Dimitri, primary, Loubersac, Sophie, additional, Reigner, Arnaud, additional, Bruneau, Alexandre, additional, Firmin, Julie, additional, François - - Campion, Valentin, additional, Kilens, Stéphanie, additional, Lelièvre, Yohann, additional, Lammers, Jenna, additional, Feyeux, Magalie, additional, Hulin, Philippe, additional, Nedellec, Steven, additional, Bretin, Betty, additional, Castel, Gaël, additional, Covin, Simon, additional, Bihouée, Audrey, additional, Soumillon, Magali, additional, Mikkelsen, Tarjei, additional, Barrière, Paul, additional, Bourdon, Jérémie, additional, Fréour, Thomas, additional, and David, Laurent, additional

Published
2019
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37. Proximity ligation in situ assay for monitoring the global DNA methylation in cells

Author

Vallette François M, Hulin Philippe, Hervouet Eric, and Cartron Pierre-François

Subjects
Global DNA methylation, method, Dnmt1/PCNA, proximity ligation in situ technology, Biotechnology, TP248.13-248.65
Abstract

Abstract Background DNA methylation has a central role in the epigenetic control of mammalian gene expression, and is required for X inactivation, genomics imprinting and silencing of retrotransposons and repetitive sequences. Thus, several technologies have been developed to measure the degree of DNA methylation. Results We here present the development of the detection of protein-protein interactions via the adaptation of the proximity ligation in situ technology to evaluate the DNA methylation status in cells since the quantification of Dnmt1/PCNA interaction in cells reflects the degree of DNA methylation. Conclusion This method being directly realizable on cells, it appears that it could suggest a wide range of applications in basic research and drug development. More particularly, this method is specially adapted for the investigations realized from a weak quantity of biologic materiel such as stem cells or primary cultured tumor cells for examples.

Published
2011
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38. Exoenzyme T Plays a Pivotal Role in the IFN-γ Production after Pseudomonas Challenge in IL-12 Primed Natural Killer Cells

Author

Vourc’h , Mickael, Roquilly , Antoine, Broquet , Alexis, David , Gaëlle, Hulin , Philippe, Jacqueline , Cédric, Caillon , Jocelyne, Retiere , Christelle, Asehnoune , Karim, Thérapeutiques Cliniques et Expérimentales des Infections, Université de Nantes ( UN ), Unité de Soins Intensifs [CHU Nantes] ( Département d'anesthésie et de soins intensifs ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications ( CRCINA - Département INCIT - Equipe 1 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Etablissement Français du Sang [Nantes], Plate-forme MicroPICell, Cell and Tissue Imaging Core [Villejuif], Structure fédérative de recherche François Bonamy ( SFR François Bonamy ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ), This work was supported by institutional funds only., Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de Soins Intensifs [CHU Nantes] (Département d'anesthésie et de soins intensifs), Centre hospitalier universitaire de Nantes (CHU Nantes), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
natural killer cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, IL-12, Pseudomonas aeruginosa, innate lymphoid cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, interferon-gamma, type III secretion system, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract

International audience; Pseudomonas aeruginosa (PA) expresses the type III secretion system (T3SS) and effector exoenzymes that interfere with intracellular pathways. Natural killer (NK) cells play a key role in antibacterial immunity and their activation is highly dependent on IL-12 produced by myeloid cells. We studied PA and NK cell interactions and the role of IL-12 using human peripheral blood mononuclear cells, sorted human NK cells, and a human NK cell line (NK92). We used a wild-type (WT) strain of PA (PAO1) or isogenic PA-deleted strains to delineate the role of T3SS and exoenzymes. Our hypotheses were tested in vivo in a PA-pneumonia mouse model. Human NK cells or NK92 cell line produced low levels of IFN-γ in response to PA without IL-12 stimulation, whereas PA significantly increased IFN-γ after IL-12 priming. The modulation of IFN-γ production by PA required bacteria-to-cell contact. Among T3SS effectors, exoenzyme T (ExoT) upregulates IFN-γ production and control ERK activation. In vivo, ExoT also increases IFN-γ levels and the percentage of IFN-γ[+] NK cells in lungs during PA pneumonia, confirming in vitro data. In conclusion, our results suggest that T3SS could modulate the production of IFN-γ by NK cells after PA infection through ERK activation.

Published
2017

39. Phosphonic Acid Fluorescent Organic Nanoparticles for High-Contrast and Selective Staining of Gram-Positive Bacteria

Author

Boucard, Joanna, primary, Boudjemaa, Rym, additional, Steenkeste, Karine, additional, Jacqueline, Cédric, additional, Stephant, Nicolas, additional, Lefèvre, François-Xavier, additional, Laurent, Adèle D., additional, Lartigue, Lénaïc, additional, Hulin, Philippe, additional, Nedellec, Steven, additional, Fontaine-Aupart, Marie-Pierre, additional, and Ishow, Eléna, additional

Published
2018
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40. Non-permissive human conventional CD1c+ dendritic cells enable trans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization.

Author

Sikorski, Mathieu, Coulon, Flora, Peltier, Cécile, Braudeau, Cécile, Garcia, Alexandra, Giraud, Matthieu, Renaudin, Karine, Kandel-Aznar, Christine, Nedellec, Steven, Hulin, Philippe, Branchereau, Julien, Véziers, Joëlle, Gaboriaud, Pauline, Touzé, Antoine, Burlaud-Gaillard, Julien, Josien, Régis, McIlroy, Dorian, Bressollette-Bodin, Céline, and Halary, Franck

Subjects
EPITHELIAL cells, DENDRITIC cells, ANTIGEN presenting cells, POLYOMAVIRUSES, NEUTRALIZATION tests, HEMATOPOIETIC stem cells, VIRAL transmission
Abstract

The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney transplant recipients (KTRs) and hematopoietic stem cell transplant recipients. In KTRs, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDCs) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived dendritic cells (MDDCs), an in vitro model for mDCs, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDCs. Endocytosed virions were efficiently transmitted to permissive cells and protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDCs from the blood and kidney parenchyma behaved similarly to MDDCs thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading. Author summary: Dr Sylvia Gardner first discovered the BK polyomavirus (BKPyV) in the urine of a kidney-transplant recipient in 1970. In the 1990's, the widespread use of potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate mofetil led to the emergence of BKPyV nephropathy. Recently, various studies reported a specific influx of myeloid dendritic cells (mDCs) in the renal tissue of kidney-transplant patients who were diagnosed with a BKPyV nephropathy. MDCs are immune cells both residing in tissues and migrating to other organs or compartments like the blood when changes in their environment occur. Their main functions are the detection of danger signals such as pathogens or tumors and the processing of antigens to prime naïve specific effectors of the adaptive immune response. Although anti-BKPyV cellular immune responses have been investigated in post-transplant recipients as well as healthy individuals, supporting an active role of mDCs little is known about how mDCs and BKPyV interact with each other. Our study provides the basis to understand the role played by mDCs in virus capture through an unprecedented endocytic mechanism and possibly in viral protection from neutralization by specific antibodies. Moreover, we showed that mDCs are unable to sense BKPyV particles or BKPyV-infected dying cells as a danger signal, supporting the view that other DC subsets might act as the true antigen presenting cells that promote the adaptive immune response against BKPyV infection. [ABSTRACT FROM AUTHOR]

Published
2021
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41. Polysaccharide Hydrogels Support the Long-Term Viability of Encapsulated Human Mesenchymal Stem Cells and Their Ability to Secrete Immunomodulatory Factors

Author

Hached, Fahd, Vinatier, Claire, Pinta, Pierre-Gabriel, Hulin, Philippe, Le Visage, Catherine, Weiss, Pierre, Guicheux, Jérôme, Billon-Chabaud, Aurélie, Grimandi, Gaël, Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université de Nantes - UFR Odontologie, PHU 11 Pharmacie [CHU Nantes] (Pharmacie Centrale), Centre hospitalier universitaire de Nantes (CHU Nantes), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Ostéo-articulaire - Tête et cou - Odontologie - Neurochirurgie - Neurotraumatologie [CHU Nantes] (Pôle hospitalo-universitaire PHU4 - OTONN), This work was supported by INSERM and grants from the Arthritis Foundation, the Research on Osteo Arthritis Diseases network (ROAD network), the research program 'Longévité Mobilité Autonomie' from the region Pays de la Loire, and a doctoral grant from the Société Française de Rhumatologie (SFR)., Jehan, Frederic, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)

Subjects
body regions, lcsh:Internal medicine, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Article Subject, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, technology, industry, and agriculture, lcsh:RC31-1245, Research Article
Abstract

International audience; While therapeutically interesting, the injection of MSCs suffers major limitations including cell death upon injection and a massive leakage outside the injection site. We proposed to entrap MSCs within spherical particles derived from alginate, as a control, or from silanized hydroxypropyl methylcellulose (Si-HPMC). We developed water in an oil dispersion method to produce small Si-HPMC particles with an average size of about 68 μm. We evidenced a faster diffusion of fluorescein isothiocyanate-dextran in Si-HPMC particles than in alginate ones. Human adipose-derived MSCs (hASC) were encapsulated either in alginate or in Si-HPMC, and the cellularized particles were cultured for up to 1 month. Both alginate and Si-HPMC particles supported cell survival, and the average number of encapsulated hASC per alginate and Si-HPMC particle (7102 and 5100, resp.) did not significantly change. The stimulation of encapsulated hASC with proinflammatory cytokines resulted in the production of IDO, PGE 2 , and HGF whose concentration was always higher when cells were encapsulated in Si-HPMC particles than in alginate ones. We have demonstrated that Si-HPMC and alginate particles support hASC viability and the maintenance of their ability to secrete therapeutic factors.

Published
2017

42. PEGylated Anionic Magneto-Fluorescent Nanoassemblies: Impact of their Interface Structure on MRI Contrast and Cellular Uptake

Author

Linot, Camille, Poly, Julien, Boucard, Joanna, Pouliquen, Daniel, Nedellec, Steven, Hulin, Philippe, Marec, Nadège, Arosio, Paolo, Lascialfari, Alessandro, Guerrini, Andrea, Sangregorio, Claudio, Lecouvey, Marc, Lartigue, Lenaic, Blanquart, Christophe, Ishow, Eléna, Bernardo, Elizabeth, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Science des Matériaux de Mulhouse (IS2M), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Dipartimento di Fisica = Department of Physics [Univ Pavia] (UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Università degli Studi di Milano = University of Milan (UNIMI), Istituto di Chimica dei Composti Organometallici (ICCOM), Consiglio Nazionale delle Ricerche (CNR), Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The 'Ligue contre le cancer 44' is gratefully acknowledged for their strong support as well as CNRS through its 'Mission pour l’Interdisciplinarité' board (program 'Nano Challenge: Health and Welfare' / ETHICAM project) and its France-Italy partnership (program PICS / MOCACINO project), and Région des Pays de la Loire through the PhD program of LUMOMAT RFI (ONASSIS project)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-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)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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 Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Department of Physics [Pavia], Università degli Studi di Pavia, Università degli Studi di Milano [Milano] (UNIMI), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)

Subjects
live cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, iron oxide nanoparticles water-soluble RAFT polymers, organic nanoparticles, spheroids, [SDV.CAN]Life Sciences [q-bio]/Cancer, fluorescence, Multimodal nanoassemblies, MRI
Abstract

International audience; Controlling the interactions of functional nanostructures with water and biological media represents high challenges in the field of bioimaging applications. Large contrast at low doses, high colloidal stability in physiological conditions, absence of cell cytotoxicity and efficient cell internalization represent strong additional needs. To achieve such requirements, we report on high payload magneto-fluorescent architectures, made of a shell of superparamagnetic iron oxide nanoparticles tightly anchored around fluorescent organic nanoparticles. Their external coating is simply modulated using anionic polyelectrolytes in a final step to provide efficient MRI and fluorescence imaging of live cells. Various structures of pegylated polyelectrolytes have been synthesized and investigated, differing from their iron oxide complexing units (carboxylic versus phosphonic acid), their structure (block or comb-like), their hydrophobicity and their fabrication process (conventional or RAFT-controlled radical polymerization) while keeping the central magneto-fluorescent platforms the same. Combined photophysical, magnetic, NMRD and structural investigations proved the superiority of RAFT polymer coatings containing carboxylate units and a hydrophobic tail to impart the magnetic nanoassemblies with enhanced-MRI negative contrast, characterized by a high r2/r1 ratio andtransverse relaxation r2 equal to 21 and 125 s-1mmol-1L respectively at 60 MHz clinical frequency (~1.5 T). Thanks to their dual modality, cell internalization of the nanoassemblies in mesothelioma cancer cells could be evidenced both by confocal fluorescence microscopy and magnetophoresis. A 72 h follow-up showed efficient uptake after 24 h with no notable cell mortality. These studies again pointed out the distinct behavior of RAFT polyelectrolyte-coated bimodal nanoassemblies that internalize at a slower rate with no adverse cytotoxicity. Extension to multicellular tumor cell spheroids that mimic solid tumors revealed successful internalization of the nanoassemblies in the periphery cells, which provides efficient deep-imaging labels thanks to their induced T2* contrast, large emission Stokes shift and bright dot-like signal, popping out of the strong spheroid autofluorescence.

Published
2017

43. DLL4 conveys Notch-dependent signals achieving selective macrophage differentiation or death

Author

Pagie, S., Pabois, Angélique, Gérard, N., Laboisse, Christian, Pattier, Sabine, Hulin, Philippe, Nedellec, Steven, Toquet, Claire, Charreau, Béatrice, Le Bihan, Sylvie, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, cardiovascular system, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Molecular mechanisms underlying vascular and inflammatory cell network at endothelial and macrophage levels are still unclear. Here we found that microvascular inflammation associates with changes in Notch signaling at endothelium/monocyte interface including loss of endothelial Notch4 and the acquisition of the Notch ligand Dll4 in both cell types. We showed that endothelial DLL4 induces circulating monocytes to polarize into a M1-type pro-inflammatory macrophages (CD40highCD64highCD200Rlow HLADRlowCD11blow) eliciting the production of IL-6. Dll4 and IL-6 are both Notch-dependent and are required for macrophage polarization through selective down and upregulation of M2and M1-type markers, respectively. Subsequently, we investigated the ability of DLL4 to interfere with M2 polarization. We found that DLL4 triggers a specific alteration of the IL-4 induced M2 phenotype through a significant inhibition of M2 markers (CD11b, CD206, CD200R). DLL4 also induces caspase3/7-dependent apoptosis specifically in M2 differentiating macrophages while DLL1 had no effect. DLL4 signals via Notch1 and DLL4mediated apoptosis is Notch-dependent. Fully differentiated M2 macrophages became resistant to DLL4 action. DLL4 upregulates gene expression, upon M2 upon differentiation, affecting the Notch pattern (Notch1, 3, Jag1) and activity (Hes1), transcription (IRF5, STAT1) that associates with decrease in Akt but not STAT6 phosphorylation. In conclusion, our findings reveal an interplay between DLL4/Notch and IL-6/IL-6R or IL-4/IL-4R signaling pathways supporting M1 differentiation and impairing M2 differentiation via apoptosis.

Published
2017

44. Hybrid Azo-fluorophore Organic Nanoparticles as Emissive Turn-on Probes for Cellular Endocytosis

Author

Boucard, Joanna, Briolay, Tina, Blondy, Thibaut, Boujtita, Mohammed, Nedellec, Steven, Hulin, Philippe, Grégoire, Marc, Blanquart, Christophe, and Ishow, Eléna

Abstract

The development of fluorescent organic nanoparticles, serving as bioimaging agents or drug cargos, represents a buoyant field of investigations. Nevertheless, their ulterior fate and structural integrity after cell uptake remain elusive. Toward this aim, we have elaborated original photoactive organic nanoparticles (dTEM∼ 35–50 nm wide) with an off–on signal upon cellular internalization. Such nanoparticles are based on the noncovalent association of red-emitting benzothiadiazole (BDZ) derivatives and azo dyes, acting as fluorescence quenchers. Upon varying the azo/BDZ ratio, we found that quantitative emission quenching could be obtained with only a 0.2:1 azo/BDZ ratio and originated from exergonic oxidative and reductive photoinduced electron transfer from the azo units (ΔelG0= −0.21 and −0.29 eV, respectively). Such results revisited the origin of emission quenching, often confusedly ascribed to Förster resonance energy transfer. A nonlinear and sharp drop of the emission intensity with the increase in the azo unit density nwas observed and presents comparable evolution to a n–1/3mathematical law. Thorough biological examinations involving cancer cells prove a receptor-independent endocytosis pathway, leading to progressive cell lighting upon nanoparticle accumulation in the late endosomal/lysosomal compartments. Complete emission recovery of the initially quenched azo/BDZ nanosystems could be achieved by using mefloquine, which caused endosomal/lysosomal disruption, and release of their content in the cytoplasm. Such results demonstrate that the dotlike emission from endosomes actually stems from fully dissociated individual dyes and not integer nanoparticles. They conclude on the high spatial confinement promoted by organelles and finally question its severe impact on functional compounds or nanoparticles whose properties are strongly distance dependent.

Published
2024
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47. Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

Author

Renand, Amédée, primary, Habes, Sarah, additional, Mosnier, Jean‐François, additional, Aublé, Hélène, additional, Judor, Jean‐Paul, additional, Vince, Nicolas, additional, Hulin, Philippe, additional, Nedellec, Steven, additional, Métairie, Sylvie, additional, Archambeaud, Isabelle, additional, Brouard, Sophie, additional, Gournay, Jérôme, additional, and Conchon, Sophie, additional

Published
2018
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49. Curcumin/poly(2-methyl-2-oxazoline-b-tetrahydrofuran-b-2-methyl-2-oxazoline) formulation: An improved penetration and biological effect of curcumin in F508del-CFTR cell lines

Author

Gonçalves, Cristine, primary, Gomez, Jean-Pierre, additional, Même, William, additional, Rasolonjatovo, Bazoly, additional, Gosset, David, additional, Nedellec, Steven, additional, Hulin, Philippe, additional, Huin, Cécile, additional, Le Gall, Tony, additional, Montier, Tristan, additional, Lehn, Pierre, additional, Pichon, Chantal, additional, Guégan, Philippe, additional, Cheradame, Hervé, additional, and Midoux, Patrick, additional

Published
2017
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50. PEGylated Anionic Magnetofluorescent Nanoassemblies: Impact of Their Interface Structure on Magnetic Resonance Imaging Contrast and Cellular Uptake

Author

Linot, Camille, primary, Poly, Julien, additional, Boucard, Joanna, additional, Pouliquen, Daniel, additional, Nedellec, Steven, additional, Hulin, Philippe, additional, Marec, Nadège, additional, Arosio, Paolo, additional, Lascialfari, Alessandro, additional, Guerrini, Andrea, additional, Sangregorio, Claudio, additional, Lecouvey, Marc, additional, Lartigue, Lénaïc, additional, Blanquart, Christophe, additional, and Ishow, Eléna, additional

Published
2017
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