Michel Salzet (Presenter)
PRISM INSERM U1192 - University of Lille
Bio: Since 1998, Professor Michel Salzet is the director of the PRISM Laboratory at the University of Lille. Pr. Salzet received his PhD in Biochemistry in 1993, where he has the Chair of Immunology since 1997. After his PhD, Pr. Salzet worked as Ass. Researcher at the Institute of Neurosciences at Old Westbury College, and was subsequently nominated as Senior Research Scientist at the Beth Israel, Mind Body Institute of Harvard Medical School. Pr. Salzet has 254 originals publications, 27 book chapters, 8 books, 16 patents (H Factor: 51). He was invited in 95 international conferences Pr. Salzet is also co-founder of the Start-Up IMABIOTECH in 2009. He was President of the French Society for Mass Spectrometry. He received in 1993 the Wicart Hagelstein Medaillon and in 2003 the “Grand Prix des Sciences” by the Science Academy of Lille, the INPI Award 2009; MATWIN in 2015.
Authorship: Stephanie Devaux(1,2), Dasa Cizkova(1,2), Jusal Quanico(1), Lena Hauberg-Lotte(3), Peter Maas(3), Jan H. Hobart(3), Isabelle Fournier(1), Michel Salzet(1)
(1) Univ. Lille, INSERM U1192 Laboratoire PRISM, Lille, France (2) Institute of Neurobiology, Slovak Academy of Sciences, Center of Excellence for Brain Research, Kosice, Slovakia (3) Center for industrial mathematics, University of Bremen, Bremen, Germany
Based on proteomics and 3D MS imaging we establish for the first time that molecular and cellular processes occurring after Spinal cord injury (SCI) are altered differently according to the lesion proximity, i.e. rostral and caudal segments nearby the lesion (R1-C1). We observe a discrepancy between R1 and C1 related to the delay in T-regulators recruitment and the presence in C1 of neurites outgrowth inhibitors (MEMO1, GFAP fragments and IgGs) that are absents in R1. The presence of IgG in neurons at very early stage of SCI may represent an additional factor contributing to the limited regeneration. Treatment in-vivo with anti-CD20 after SCI does not improve locomotor functions whereas using alginate filled with RhoA inhibitor promote regeneration. These results open the door of a novel view of the SCI treatment by considering the C1 as the therapeutic target.
Spinal cord injury (SCI) belongs to the serious, currently incurable disorders of the central nervous system (CNS), that are often accompanied by a permanent disability. Most SCI are related to traumatic spinal cord damages induced by road trauma, falls, or sport injuries (diving). Among the hallmark features of SCI is the axonal disruption in the spinal cord, which is often caused by fractured intervertebral disc or vertebrate. This primary event is followed by a progressive cascade of secondary deleterious reactions spreading to the adjacent spared tissue leading to a worsening of the neurological status. Although axonal regeneration is initiated, it is hampered by a combination of local factors that include severe inflammation, lack of trophic support and development of an inhibitory scar-forming environment. In fact, the regenerative capacity of the central nervous system is particularly challenged in SCI as multiple cues converge to act as a chemical and physical barrier for the repair process. It is now acknowledged that inflammation is one of the major key player that determines abortive axonal repair in SCI. Thus, while the immune response is recognized as primordial to preserve tissue homeostasis, the spatio-temporal course of inflammation in SCI is not favorable to axonal regeneration.
In this context, a large array of molecules and therapies has been tested experimentally with the goal of targeting the healthy tissue adjacent to spinal cord lesion. Such a strategy is aimed at not only protecting this spared tissue from secondary lesion but also stimulating its regenerative potential in order to promote neuronal networks connectivity and axonal outgrowth. Among these proposed therapeutic strategies, cellular therapy belongs to the promising candidate approaches. Ideally, cell therapy strategies may allow to: i) bridge spinal cord segments over any cavities or cysts formed at the lesion site, ii) replace lost neurons, oligodendroglia and iii) create a favorable environment for axonal regeneration. Different cell therapy approaches include embryonic stem cells, induced pluripotent stem cells (iPS) and different categories of adult stem cells and progenitors such as olfactory unsheathing stem cells, neural progenitors cells (NPC) and mesenchymal stem cells (MSCs). In addition, graft of activated macrophages and transplantation of peripheral or central nervous tissue have been also proposed as an alternative to these stem cells based treatments. Comparative to cell therapy, other approaches including the use of exogenously-delivered neuroprotective molecules that would protect neurons from deleterious secondary processes, promote axonal growth and/or enhance nerve conduction in the preserved or regenerating axons. Different classes of molecules were shown to afford variable levels of clinical recovery in animal models of SCI. These comprise anti-inflammatory compounds such as minocycline, neurotrophic factors (BDNF, GDNF, NGF, and erythropoietin) and molecules that alleviate regenerating axons from the inhibitory effects of extracellular matrix molecules. In particular, chondroitinase ABC eliminates chondroitin sulfate proteoglycans (CSPG) that interact with the major membranous component NG2 and inhibit the regeneration of damaged axons. Also, Nogo-A is one of several neurite growth inhibitory receptors expressed by axons. Thereby Nogo neutralizing antibodies or blockers of the post-receptors components of RhoA are used to improve long-distance axon regeneration and sprouting. Of note, Rho pathway is important to control the neuronal response after CNS injury and the RhoA inhibitor cethrin is actually in phase I/II a clinical trial. However, although numerous therapies exhibit potentials to foster neuroprotection, stimulate neurite outgrowth and reduce inflammation, the translation to clinical side is still not crowned by success. Reasons for such a failure are multiple and reside notably in our relatively poor knowledge on the spatiotemporal kinetics of secondary molecular events that characterize the post-trauma phase. This holds particularly important with regard to inflammatory mechanisms that may greatly vary depending on the time point and spinal cord segment considered. Defining a time- and segment-specific window for effective treatment is a key knowledge for an appropriate neuro-therapeutic intervention.
Here we present the first exhaustive spatio-temporal proteomic and biochemical analysis performed along the entire spinal cord axis in rat model of SCI (1). We combined this global proteomic analysis with 3D molecular mass spectrometry imaging study, time course analysis of immune cells infiltration and cytokine microarrays quantification. The whole spectrum of the data allowed us to depict a complete scheme along the spinal cord axis of the cellular and molecular sequel of events occurring through the time course of inflammatory process and abortive regeneration. We identified specific markers for each segment at different time points (3, 7 and 10 days) of the biochemical-pathophysiological processes and observed that, surprisingly, rostral and caudal segments nearby the lesion (R1-C1) express inflammatory factors whereas distant segments (R2-C2 and R3-C3) co-express factors implicated in neurogenesis (2). We also observe a discrepancy between R1 and C1 related to the delay in T-regulators recruitment and the presence in C1 of neurites outgrowth inhibitors (MEMO1, lectins, GFAP fragments and IgGs) that are absents in R1. The presence of IgG in neurons at very early stage of SCI may represent an additional factor contributing to the limited regeneration. We provided evidence that immunoglobulins are present at the lesion site at 1 day after injury and that in vivo treatment of anti-CD20 did not diminished the presence of these antibodies and did not ameliorate the BBB score of the treated animals. By contrast, using alginate filled with RhoA inhibitor we can observe a stimulation of regeneration. These results open the door of a novel view of the SCI treatment by considering the C1 as the therapeutic target combine with the use of a smart biomaterial with RhoA inhibitor and Stem Cells (3-5).
References & Acknowledgements:
1. Cizkova, D., Le Marrec-Croq, F., Franck, J., Slovinska, L., Grulova, I., Devaux, S., Lefebvre, C., Fournier, I., and Salzet, M. (2014) Alterations of protein composition along the rostro-caudal axis after spinal cord injury: proteomic, in vitro and in vivo analyses. Front Cell Neurosci 8, 105
2. Devaux, S., Cizkova, D., Quanico, J., Franck, J., Nataf, s., Pays, L., Lotte, L. H., Maas, P., Kobart, J. H., Kobeissy, F., Meriaux, c., Wisztorski, M., Slovinska, L., Blasko, J., Cigankova, V., Fournier, I., and Salzet, M. (2016) Spatial and temporal 3D MSI and proteomic studies of rat spinal cord injury: Evidence of caudal segment for possible therapy target. Molecular & Cellular Proteomics
3. Cizkova, D., Devaux, S., Le Marrec-Croq, F., Franck, J., Slovinska, L., Blasko, J., Rosocha, J., Spakova, T., Lefebvre, C., Fournier, I., and Salzet, M. (2014) Modulation properties of factors released by bone marrow stromal cells on activated microglia: an in vitro study. Scientific reports 4, 7514
4. Cizkova, D., Devaux, S. p., Le Marrec-Croq, F. o., Franck, J., Slovinska, L., Blasko, J., Rosocha, J., Spakova, T., Lefebvre, C., and Fournier, I. (2014) Modulation properties of factors released by bone marrow stromal cells on activated microglia: an in vitro study. Scientific reports 4
5. Slovinska, L., Szekiova, E., Blasko, J., Devaux, S., Salzet, M., and Cizkova, D. (2015) Comparison of dynamic behavior and maturation of neural multipotent cells derived from different spinal cord developmental stages: an in vitro study. Acta neurobiologiae experimentalis 75, 107-114
IP Royalty: no
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