PI:  Anne Baron Van Evercooren  and Brahim Nait Oumesmar    

INSTITUTE  Institut du Cerveau et de la Moelle Epinière (ICM), INSERM

ADDRESS 47 Boulevard Hôpital, 75013 Paris, France

WEB ICM - Hôpital Pitié Salpêtrière

The Baron-Van Evercooren and Nait Oumesmar laboratories have both made significant contributions to elucidating the molecular and cellular processes involved in myelination, demyelination and remyelination. The Baron-Van Evercooren lab has focused on “molecular and cellular approaches of myelin repair” and made important contributions to the understanding of remyelination in the CNS and in the development of in line therapeutic approaches. Through the use of skills in cell culture, animal models of demyelination and transplantation paradigms, the lab has (i) defined the contribution of adult neural stem cells to oligodendrogenesis during myelin repair;147-149 (ii) developed models of demyelination in primates;150 (iii) substantially contributed to establish the role of exogenous human CNS neural stem cells63,136,151 and rodent PNS stem cells in remyelination152-154. The lab is now involved in defining the molecular and cellular – intrinsic and extrinsic - mechanism(s) sustaining myelin repair by both endogenous and transplanted NPCs using animal models of myelination and focal demyelination of the mouse spinal cord as well as established myelin mutant mouse models. Furthermore, the lab has gained expertise in the field of hiPSCs transplantation in rodent138  (Herlich and Mozafari et al., submitted). Namely, reprogrammed pluripotent lines generated from healthy and MS affected individuals and their differentiated derivatives generated by the Martino and Kuhlmann’s groups are currently a matter of active investigation from a therapeutic and biological point of view.

Pertinent to the proposal, the Baron-Van Evercooren lab will contribute to the project by (1) characterizing in vitro the molecular profile of human fetal and iPSC derived-OPCs from HC and MS comparing them with human fetal cells; 2) testing the response of fetal and iPSC-derived hOPCs to myelin promoting factors in vitro in dissociated cultures or in combination with myelin promoting factors; 3) testing in vivo in animal model of dysmyelination (neonate/adult LPC treated Shiverer mice) the pro-myelinating effects of selected molecules on human exogenous iOPCs from both HC and MS patients (chimeric rodent-human mice) and compare their response to fetal hOPCs. The Nait Oumesmar lab focuses on mechanisms of oligodendrocyte development and regeneration. The lab has made important contributions to the mechanisms of myelin regeneration and the development of experimental therapeutic to promote (re)-myelination. The Nait Oumesmar lab has defined: i) the contribution of adult neural stem cells to myelin repair,147,155 ii) the role of Olig2, RXRg, Vitamin D receptor and Sox17 in oligodendrocyte development in animal models and in MS lesions55,59,156-158 and of the tocopherol TFA-12 as new promyelinating compound in experimental models of MS.135 The laboratory has a strong expertise in molecular biology, transcriptional regulation of oligodendrocyte specification and differentiation during CNS development and repair, and high content screening of small compounds promoting OPC differentiation. The team has also a recognized expertise in transgenic mouse models and lentiviral technology. B. Nait Oumesmar has published over 48 original papers in high impact journals, including Nature Neuroscience, Neuron, Journal of Clinical Investigation, PNAS and Brain. The Nait Oumesmar team has recently graded “excellent” by an international Scientific Advisory Board. Pertinent to this proposal, the Nait Oumesmar lab will contribute with an innovative double fluorescence OPC line for high content screening of compounds inducing differentiation. The lab will further help the development of this reporter assay in human cells. The lab will be in charge of the high content screen of the effects of candidate therapeutic compounds using the double fluorescent CG4 cell line (WP2) and of the preclinical validation of lead compounds in the focal model of lysolecithin-induced demyelination (WP6). The Baron-Van Evercooren and Nait Oumesmar laboratories are member of the Brain and Spine Institute (http;//icm-institute.org) a research center of international dimensions, innovative both by the design and the organization, located in the Pitié-Salpêtrière University Hospital, one the most prestigious medical school in Europe with a strong tradition in Neurology, and MS in particular.

double fluorescent OPC line, mCherry in differentiated oligodendrocytes   and GFP in all stages of the lineage