Endothelin modulates both short-term kinetics of odorant detection and long-term cellular population dynamics in olfactory mucosa

International audienc

Endothelin evokes distinct calcium transients in neuronal and non-neuronal cells of rat olfactory mucosa primary cultures

International audienceThe olfactory system is regulated by several nervous and hormonal factors, and there is a growing body of evidence that some of these modulations already take place in the olfactory mucosa (OM). We recently suggested that, among others, vasoactive peptides might play multifaceted roles in different OM cells. Here we studied the effect of the vasoconstrictive peptide endothelin (ET) in the rat OM. We identified different components of the ET system both in the olfactory mucosa and in long-term primary culture of OM cells, composed of olfactory sensory neurons (OSNs) lying on a blend of non-neuronal OM cells (nNCs). We demonstrated that ET receptors are differentially expressed on OM cells, and that ET might be locally matured by the endothelin-converting enzyme ECE-1 located in OSNs. Using calcium imaging, we showed that ET triggers robust dose-dependent Ca(2+) responses in most OM cells, which consist of a transient phase, followed, in nNCs, by a sustained plateau phase. All transient responses depended on intracellular calcium release, while the sustained plateau phase also depended on subsequent external calcium entry. Using both pharmacology and spotting lethal (sl/sl) mutant rats, lacking functional ET(B) receptors, we finally demonstrated that these effects of ET are mediated through ET(B) receptors in OSNs and ET(A) receptors in nNCs. The present study therefore identifies endothelin as a potent endogenous modulator of the olfactory mucosa; specific endothelin-mediated Ca(2+) signals may serve distinct signaling functions, and thereby suggest differential functional roles of endothelin in both neuronal and non-neuronal OM cells

Short-term effects of endothelin in rat olfactory mucosa : modulation of odorant detection and intercellular communication

National audienc

Contribution of CLEM to study the PAH-related pulmonary vasculary remodeling

absen

Concise Review: Pluripotent Stem Cell-Derived Cardiac Cells, A Promisingă Cell Source for Therapy of Heart Failure: Where Do We Stand?

International audienceHeart failure is still a major cause of hospitalization and mortality ină developed countries. Many clinical trials have tested the use ofă multipotent stem cells as a cardiac regenerative medicine. The benefită for the patients of this therapeutic intervention has remained limited.ă Herein, we review the pluripotent stem cells as a cell source foră cardiac regeneration. We more specifically address the variousă challenges of this cell therapy approach. We question the cell deliveryă systems, the immune tolerance of allogenic cells, the potentială proarrhythmic effects, various drug mediated interventions to facilitateă cell grafting and, finally, we describe the pathological conditions thată may benefit from such an innovative approach. As members of aă transatlantic consortium of excellence of basic science researchers andă clinicians, we propose some guidelines to be applied to cell types andă modes of delivery in order to translate pluripotent stem cell cardiacă derivatives into safe and effective clinical trials

Endothelin modulates both short-term detection kinetics of odors and long-term cellular population dynamics in olfactory mucosa

International audienc

0245: Cell therapy to restore overloaded right ventricular function: First promising results using human cardiac progenitors seeded in a patch on the epicardium

BackgroundDespite the prevalence of right ventricular (RV) failure in congenital heart diseases, cell therapy applied to RV is poorly studied. Our aim is to evaluate in a large animal model of overloaded RV dysfunction such therapy using cardiac progenitors (CP) issued from human embryonic stem cells.MethodsA combined overloaded RV dysfunction was created in pigs using a surgical procedure mimicking repaired tetralogy of Fallot. At 4 months, cell therapy was surgically administrated using either multiple transepicardial injections of HUES-24 derived CP into RV myocardium or CP seeded collagen patches sewn on RV free wall. SHAM animals received either multiple transepicardial injections of medium or acellular patches. Myocardial function was determined 3 months later by conductance catheter technique with maximal elastance (Emax) slope. Ventricular arrhythmia risks were tested by programmed ventricular stimulation. A histological study analyzed the structural remodelling. CP fate was studied using anti- Ki67, CD31, CD34, GFP, Islet1 and Connexin 43 antibodies. All pigs were immunosuppressed by Tacrolimus.ResultsAll pigs survived. Neither complication nor ventricular arrhythmia occurred. In injected animals (SHAM: n=6, HUES-24: n=6) the Emax slope value evoluated similarly in both groups. Whereas total fibrosis increased significantly with time in the SHAM group, it returned to baseline in HUES-24 group. However, CP could not be found. In contrast, in patched animals, CP were found in the patch zone and close to the myocardium. These CP were able to proliferate, migrate, express cardiac markers and establish connexions.ConclusionCell therapy using transepicardial injections of human CP seems to have a beneficial effect on overloaded RV tissue remodelling, but this administration mode did not improve myocardial contractility. Seeded patches seem to be more conservative for engrafted cells; their impact on overloaded RV function requires further experiments

Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy.

International audienceMembranous nephropathy is a glomerular disease typified by a nephrotic syndrome without infiltration of inflammatory cells or proliferation of resident cells. Although the cause of the disease is unknown, the primary pathology involves the generation of autoantibodies against antigen targets on the surface of podocytes. The mechanisms of nephrotic proteinuria, which reflect a profound podocyte dysfunction, remain unclear. We previously found a new gene, c-mip (c-maf-inducing protein), that was associated with the pathophysiology of idiopathic nephrotic syndrome. Here we found that c-mip was not detected in the glomeruli of rats with passive-type Heymann nephritis given a single dose of anti-megalin polyclonal antibody, yet immune complexes were readily present, but without triggering of proteinuria. Rats reinjected with anti-megalin develop heavy proteinuria a few days later, concomitant with c-mip overproduction in podocytes. This overexpression was associated with the downregulation of synaptopodin in patients with membranous nephropathy, rats with passive Heymann nephritis, and c-mip transgenic mice, while the abundance of death-associated protein kinase and integrin-linked kinase was increased. Cyclosporine treatment significantly reduced proteinuria in rats with passive Heymann nephritis, concomitant with downregulation of c-mip in podocytes. Thus, c-mip has an active role in the podocyte disorders of membranous nephropathy

G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration

OBJECTIVES: The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. METHODS: We combined in vivo systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation. RESULTS: We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. INTERPRETATION: Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders