Differentiation, stem cells and prions - NSERM UMR-S747, Université Paris Descartes, 45 rue des Saints-Pères, 75006  


  HEADKELLERMANN Odile / odile.kellermann@pasteur.fr
  MEMBERSOdile KELLERMANN (PRCE- ENS Ulm - Paris XI) / Anne POLIARD (PR2 Ecole dentaire) / Sophie MOUILLET-RICHARD (Ministère de l’Agriculture ICGREF, détachée à l’INSERM) / Benoît SCHNEIDER (CR1-CNRS, chargé de cours à l’Ecole polytechnique) / Catherine VIDAL(chef de laboratoire, Institut Pasteur) / Marie Noëlle Monier (IE CNRS) / Hector Ardila (ITA Paris Descartes) / Mathéa PIETRI (Post-Doc, agrégée-préparatrice ENS Ulm) / Anne Baudry (Post-Doc, CDD Junior INSERM) / Elodie Pradines, ( Doct 4ème année, bourse AMX, moniteur Paris 6, au 1/1/09 bourse FRM) / Damien Loubet ( Doct 2ème année -ED Paris 11- bourse AMX moniteur Paris Descartes) / Yassine Harichane (Doct 2ème année, A-HU Faculté de Chirurgie Dentaire Paris-Descartes) / Arnaud Marchadier (Doct 2ème année, bourse CIFRE en collaboration avec S. Ordureau, Usefullprogres, Imagerie 3D par scanner aux rayons X) / Sasha Dimitrova (Doct 1ère année, A-HU Faculté de Chirurgie Dentaire Paris-Descartes) / Caroline Dakowski (M2, Paris Descartes, Biologie Cellulaire-Physiologie-Pathologie)


  Annual Report

The central topic of our research deals with the mechanisms that control stem cell differentiation. We exploit the properties of a neuroectodermal (1C11) and a mesenchymal (C1) progenitor isolated from multipotent embryonal cells. Both clones display the properties of stem cells, and may engage upon appropriate induction into differentiation programs up to the acquisition of specialized functions. Their alternative fates are mutually-exclusive and recruit nearly 100% cells.

The 1C11 cell line to study neuronal homeostasis and prion physiopathology:

1C11 cells can convert into fully-functional serotonergic (1C115-HT ) or noradrenergic (1C11 NE) neuronal cells. The implementation of neuronal functions is regulated by external serotonin (5-HT) or noradrenaline (NE) through autoreceptors selectively induced along either pathway. Our aim is to characterize the signaling pathways, the targets and the crosstalks associated with the receptors to unravel how these autoreceptors contribute to the homeostasis of 5-HT or NE functions. Indeed, we have shown that the 5-HT2B receptor controls the onset and functionality of the 5-HT transporter. In addition, we have established a functional link between the bioaminergic 5-HT2B and α1D receptors and the production of reactive oxygen species, the shedding of TNFα, and the metabolism of 5-HT or NE in 1C11 5-HTand 1C11NE neuronal cells.

The 1C11 cell line has been instrumental in assigning a signaling function to the cellular prion protein PrP C. This year, we have identified new PrPC -dependent signal transduction effectors such as CREB transcription factor and its target genes (Egr1, c-fos, MMP9.. ) in neuronal cells which provides a foundation for elucidating how the deviation of PrPCnormal function may lead to prion diseases

Using the prion neurotoxic peptide PrP106-126 to mimic prion infection, we have established that PrP106-126 exerts a toxic action that is restricted to neuronal cells. By binding to normal PrPC , PrP106-126 corrupts the normal signaling pathway coupled with PrPCand recruits apoptotic cascasdes.

1C11 cells support the replication of various prion strains. Pathogenic prions alter monoaminergic functions and trigger the production of oxidized derivatives of serotonin or catecholamines. We recently identified these bioamine oxidation products as neurotoxins, which interfere with neurotransmitter-associated enzymesthrough oxidative attack.

C1 cells and bone mineralization:

The C1 clone is a tripotential mesoblastic progenitor with osteogenic, chondrogenic or adipogenic potencies. We recently identified a critical role of the 5-HT2B serotonergic receptor in mineralization through full control of tissue-non specific alkaline phosphatase activity (TNAP). Preliminary data indicate that in patients suffering from ectopic vascular mineralization, the degree of calcification correlates with the level of 5-HT2BR expression.

We are developping a 3D scanner imaging project allowing longitudinal studies to unravel phenotypic defects in genetically modified mice (monitoring of bone mineral density, dental and cranio-facial defects, adipose tissue distribution, lung morphology…).

We isolated dental pulp progenitor cell lines with distinct differentiation potentials. We are currently exploiting these clones to set up dental repair protocols.

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  Publications

Pietri M., Schneider B, Mouillet-Richard S, Ermonval M, V Mutel, J.M Launay and O Kellermann. (2005) Reactive oxygen species-dependent TNF-α converting enzyme activation through stimulation of 5-HT2B and α D autoreceptors in neuronal cells. FASEB J, 19,1078-1087. PMID: 15985531

Locker M, J Bitard, C Collet, A Poliard, V Mutel, J.M Launay and O Kellermann. (2006) Stepwise control of osteogenic differentiation by 5-HT2B receptor signalling: Nitric oxyde production and phospholipase A2 activation. . Cell Signal. 2006;18(5):628-39. PMID: 16014328

Launay J.M., Schneider B, Loric S., Da Prada M. & Kellermann O. Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB, 20(11):1843-54. PMID: 16940156

Pietri M., Caprini A,, Mouillet-Richard S, Pradines E, Ermonval M .,Grassi J., O Kellermann and B Schneider. (2006) Overstimulation of PrPC signaling pathways by prion peptide 106-126 causes oxydative injury of 1C11 bioaminergic neuronal cells. J. Biol Chem, 281(38):28470-9. PMID: 16864581

Mouillet-Richard S, Nishida N, Pradines E, Laude H, Schneider B, Feraudet C, Grassi J, Launay JM , Lehmann S and O Kellermann. (2008) Prions impair bioaminergic functions through serotonergic- or catecholaminergic-derived neurotoxins in neuronal cells. J. Biol. Chem, 283, 23782-23790. PMID: 18617522





Activity Reports 2009 - Institut Pasteur
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