Synthesis of Deployment Results (Deliverable 4.6, Univerself)

Project DeliverableInternational audienceThis deliverable presents the synthesis of intermediate deployment results part of the Univerself project. Full list of authors per institution: ALBLF: Leila Bennacer, Benoit Ronot, Laurent Ciavaglia FT: Zwi Altman, Christian Destré INRIA: Remi Badonnel, Martin Barrere, Olivier Festor NEC: Johannes Lessmann, Zarrar Yousaf, Paulo Loureiro NKUA: Eleni Patouni, Vangelis Kosmatos, George Katsikas, Roi Arapoglou, Kostas Chatzikokolakis, Alex Apostolidis, Nancy Alonistioti TI: Antonio Manzalini TID: Beatriz Fuentes UNIS: Majid Ghader UPRC: Panagiotis Demestichas, Kostas Tsagkaris, Giorgios Poulios, Vasilis Foteinos, Aimilia Bantouna, Panagiotis Vlacheas, Vera Stavroulaki, Yiouli Kritikou, Dimitris Kelaidonis, Marios Logothetis, Dimitris Karvounas, Andreas Georgakopoulos, Louisa Papadopoulou, Assimina Sarli, Evangelia Tzifa UT: Ramin Sadre VTT: Teemu Rautio, Jukka Mäkelä, Petteri Mannersal

PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury

International audienceMyocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ / δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ / δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.10 5 , 6.10 5 , and 24.10 5 cells / heart) and the dose of 6.10 5 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ / δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ / δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ / δ-dependent but not related to their anti-inflammatory effects

TAFA4, a Chemokine-like Protein, Modulates Injury-Induced Mechanical and Chemical Pain Hypersensitivity in Mice

C-low-threshold mechanoreceptors (C-LTMRs) are unique among C-unmyelinated primary sensory neurons. These neurons convey two opposite aspects of touch sensation: a sensation of pleasantness, and a sensation of injury-induced mechanical pain. Here, we show that TAFA4 is a specific marker of C-LTMRs. Genetic labeling in combination with electrophysiological recordings show that TAFA4+ neurons have intrinsic properties of mechano-nociceptors. TAFA4-null mice exhibit enhanced mechanical and chemical hypersensitivity following inflammation and nerve injury as well as increased excitability of spinal cord lamina IIi neurons, which could be reversed by intrathecal or bath application of recombinant TAFA4 protein. In wild-type C57/Bl6 mice, intrathecal administration of TAFA4 strongly reversed carrageenan-induced mechanical hypersensitivity, suggesting a potent analgesic role of TAFA4 in pain relief. Our data provide insights into how C-LTMR-derived TAFA4 modulates neuronal excitability and controls the threshold of somatic sensation

The stress-induced transcription factor NR4A1 adjusts mitochondrial function and synapse number in prefrontal cortex

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders

Le péri-urbain en Aquitaine

En 1977 était lancée une étude sur l’habitat individuel périurbain. Elle devait analyser les principaux problèmes créés par le développement très rapide des zones péri-urbaines, notamment sous la forme d’habitat individuel. Présidée par Jacques MAYOUX, inspecteur général des finances, la mission d’étude remit son rapport final le 21 mars 1979 au Ministre de l’Environnement et du Cadre de vie de l’époque, Michel d’Ornano. En 1981, l’Établissement Public Régional d’Aquitaine lançait une étude sur les conditions de développement d’une politique régionale contractuelle destinée aux zones péri-urbaines de ses principales agglomérations. L’équipe d’étude constituée à cet effet rendait ses conclusions au mois d’avril 1983. Entre ces deux évènements, l’un national, l’autre régional, qui marquent au moins les préoccupations sinon l’embarras ou l’impuissance des responsables face au développement des agglomérations et aux formes urbaines que prend ce développement, avec toutes les conséquences économiques et sociales qui s’ensuivent, quelles relations existe-t-il ou quels éléments du rapport Mayoux expliquent, éclairent ou justifient le questionnement sur le péri-urbain en Aquitaine