6 research outputs found
Effet de la stimulation magnétique répétitive trans-spinale comme thérapie non invasive dans le cadre des lésions médullaires.
Spinal cord injury (SCI) leads to a loss of sensitive and motor functions. Currently, there is no therapeutic intervention offering a complete recovery. Here, we report that repetitive trans-spinal magnetic stimulation (rTSMS) can be a noninvasive SCI treatment that enhances tissue repair and functional recovery. Several techniques including immunohistochemical, behavioral, cells cultures, and proteomics have been performed. Moreover, different lesion paradigms, such as acute and chronic phase following SCI in wild-type and transgenic animals at different ages (juvenile, adult, and aged), have been used. We demonstrate that rTSMS modulates the lesion scar by decreasing fibrosis and inflammation and increases proliferation of spinal cord stem cells. Our results demonstrate also that rTSMS decreases demyelination, which contributes to axonal regrowth, neuronal survival, and locomotor recovery after SCI. This research provides evidence that rTSMS induces therapeutic effects in a preclinical rodent model and suggests possible translation to clinical application in humans.Les lĂ©sions de la moelle spinale constituent un problĂšme de santĂ© public dâune ampleur grandissante. Bien que lâespĂ©rance de vie ait Ă©tĂ© amĂ©liorĂ©e, les patients mĂ©dullo-lĂ©sĂ©s souffrent de certains handicaps entraĂźnant une perte partielle ou complĂšte des fonctions sensorielles et/ou motrices. La moelle spinale lĂ©sĂ©e entreprend aussitĂŽt une rĂ©ponse Ă cette lĂ©sion. Chronologiquement, la lĂ©sion se divise en deux grandes phases : la phase primaire qui se caractĂ©rise par la destruction tissulaire induite par le traumatisme mĂ©canique, suivie dâune destruction cellulaire. Alors que la phase secondaire est la consĂ©quence molĂ©culaire et cellulaire de la phase primaire. Durant plusieurs annĂ©es, diffĂ©rentes stratĂ©gies thĂ©rapeutiques ont Ă©tĂ© proposĂ© principalement la thĂ©rapie cellulaire qui a prouvĂ© ses effets bĂ©nĂ©ïŹques dans diffĂ©rents modĂšles expĂ©rimentaux de la lĂ©sion , mais de nombreux obstacles sont Ă prendre en considĂ©ration tel que, principalement, son caractĂšre invasif. aïŹn de pouvoir lâappliquer chez lâhomme dâune maniĂšre efficace et reproductible . A la vue de ces contraintes cliniques, nous avons dĂ©cidĂ© dâexplorer un traitement non invasif connu pour ses effets neuroprotecteurs et neurotrophiques dans le SNC ; la stimulation magnĂ©tique rĂ©pĂ©titive trans-spinale (rTSMS). Etonnement, peu dâĂ©tudes ont explorĂ© cette thĂ©rapie dans le cadre des LMTs, et rare sont celles qui lâont utilisĂ© dâune maniĂšre focale, câest Ă dire directement au niveau du site de la lĂ©sion. A ce jour, les mĂ©canismes et les voies sous-jacentes de ces effets dans ce cadre restent toujours inconnus. Câest pourquoi nous avons entrepris de caractĂ©riser ces effets dans le cadre de mes travaux de ThĂšse. En effet, en premier lieu, nous avons Ă©valuĂ© les effets de la rTSMS sur la rĂ©paration tissulaire, via la modulation de la cicatrice mĂ©dullaire et de ces diffĂ©rentes composantes in vivo, ainsi que sur la rĂ©cupĂ©ration fonctionnelle dans diffĂ©rents paradigmes (aigue et chronique) et Ă diffĂ©rents Ăąges (juvĂ©nile, adulte et vieux) chez des souris WT ayant subi une transsection complĂšte de la moelle spinale. En second lieu, lâobjectif Ă©tait de dĂ©crire les mĂ©canismes Ă lâorigine des effets de la rTSMS. Pour ce faire, des analyses protĂ©omiques ont Ă©tĂ© rĂ©alisĂ©es, puis nous avons Ă©valuĂ© lâeffet de la rTSMS sur la rĂ©activitĂ© des cellules souches endogĂšnes de la moelle, ainsi que, la contribution de ces derniĂšres dans la mise en place de la cicatrice gliale in vitro et in vivo via un modĂšle de souris transgĂ©nique hFoxJ1-CreER T2 ::tdTomato. Lâobjectif global Ă©tait dâĂ©tudier, pour la premiĂšre fois, lâeffet de la rTSMS sur la rĂ©ponse des diffĂ©rentes composantes cellulaires rĂ©sidentes de la moelle spinale, les mĂ©canismes Ă lâorigine de ces effets, ainsi que la capacitĂ© Ă restaurer les fonctions motrices perdues suite Ă la lĂ©sion mĂ©dullaire
The Regenerative Effect of Trans-spinal Magnetic Stimulation After Spinal Cord Injury : Mechanisms and Pathways Underlying the Effect
Les lĂ©sions de la moelle spinale constituent un problĂšme de santĂ© public dâune ampleur grandissante. Bien que lâespĂ©rance de vie ait Ă©tĂ© amĂ©liorĂ©e, les patients mĂ©dullo-lĂ©sĂ©s souffrent de certains handicaps entraĂźnant une perte partielle ou complĂšte des fonctions sensorielles et/ou motrices. La moelle spinale lĂ©sĂ©e entreprend aussitĂŽt une rĂ©ponse Ă cette lĂ©sion. Chronologiquement, la lĂ©sion se divise en deux grandes phases : la phase primaire qui se caractĂ©rise par la destruction tissulaire induite par le traumatisme mĂ©canique, suivie dâune destruction cellulaire. Alors que la phase secondaire est la consĂ©quence molĂ©culaire et cellulaire de la phase primaire. Durant plusieurs annĂ©es, diffĂ©rentes stratĂ©gies thĂ©rapeutiques ont Ă©tĂ© proposĂ© principalement la thĂ©rapie cellulaire qui a prouvĂ© ses effets bĂ©nĂ©ïŹques dans diffĂ©rents modĂšles expĂ©rimentaux de la lĂ©sion , mais de nombreux obstacles sont Ă prendre en considĂ©ration tel que, principalement, son caractĂšre invasif. aïŹn de pouvoir lâappliquer chez lâhomme dâune maniĂšre efficace et reproductible . A la vue de ces contraintes cliniques, nous avons dĂ©cidĂ© dâexplorer un traitement non invasif connu pour ses effets neuroprotecteurs et neurotrophiques dans le SNC ; la stimulation magnĂ©tique rĂ©pĂ©titive trans-spinale (rTSMS). Etonnement, peu dâĂ©tudes ont explorĂ© cette thĂ©rapie dans le cadre des LMTs, et rare sont celles qui lâont utilisĂ© dâune maniĂšre focale, câest Ă dire directement au niveau du site de la lĂ©sion. A ce jour, les mĂ©canismes et les voies sous-jacentes de ces effets dans ce cadre restent toujours inconnus. Câest pourquoi nous avons entrepris de caractĂ©riser ces effets dans le cadre de mes travaux de ThĂšse. En effet, en premier lieu, nous avons Ă©valuĂ© les effets de la rTSMS sur la rĂ©paration tissulaire, via la modulation de la cicatrice mĂ©dullaire et de ces diffĂ©rentes composantes in vivo, ainsi que sur la rĂ©cupĂ©ration fonctionnelle dans diffĂ©rents paradigmes (aigue et chronique) et Ă diffĂ©rents Ăąges (juvĂ©nile, adulte et vieux) chez des souris WT ayant subi une transsection complĂšte de la moelle spinale. En second lieu, lâobjectif Ă©tait de dĂ©crire les mĂ©canismes Ă lâorigine des effets de la rTSMS. Pour ce faire, des analyses protĂ©omiques ont Ă©tĂ© rĂ©alisĂ©es, puis nous avons Ă©valuĂ© lâeffet de la rTSMS sur la rĂ©activitĂ© des cellules souches endogĂšnes de la moelle, ainsi que, la contribution de ces derniĂšres dans la mise en place de la cicatrice gliale in vitro et in vivo via un modĂšle de souris transgĂ©nique hFoxJ1-CreER T2 ::tdTomato. Lâobjectif global Ă©tait dâĂ©tudier, pour la premiĂšre fois, lâeffet de la rTSMS sur la rĂ©ponse des diffĂ©rentes composantes cellulaires rĂ©sidentes de la moelle spinale, les mĂ©canismes Ă lâorigine de ces effets, ainsi que la capacitĂ© Ă restaurer les fonctions motrices perdues suite Ă la lĂ©sion mĂ©dullaire.Spinal cord injury (SCI) leads to a loss of sensitive and motor functions. Currently, there is no therapeutic intervention offering a complete recovery. Here, we report that repetitive trans-spinal magnetic stimulation (rTSMS) can be a noninvasive SCI treatment that enhances tissue repair and functional recovery. Several techniques including immunohistochemical, behavioral, cells cultures, and proteomics have been performed. Moreover, different lesion paradigms, such as acute and chronic phase following SCI in wild-type and transgenic animals at different ages (juvenile, adult, and aged), have been used. We demonstrate that rTSMS modulates the lesion scar by decreasing fibrosis and inflammation and increases proliferation of spinal cord stem cells. Our results demonstrate also that rTSMS decreases demyelination, which contributes to axonal regrowth, neuronal survival, and locomotor recovery after SCI. This research provides evidence that rTSMS induces therapeutic effects in a preclinical rodent model and suggests possible translation to clinical application in humans
Spinal cord injury: can we repair spinal cord non-invasively by using magnetic stimulation?
International audienceSpinal cord injury (SCI) is an incurable condition in which the brain is disconnected partially or completely from the periphery. Mainly, SCIs are traumatic and are due to traffic, domestic or sport accidents. To date, SCIs are incurable and, most of the time, leave the patients with a permanent loss of sensitive and motor functions. Therefore, for several decades, researchers have tried to develop treatments to cure SCI. Among them, recently, our lab has demonstrated that, in mice, repetitive trans-spinal magnetic stimulation (rTSMS) can, after SCI, modulate the lesion scar and can induce functional locomotor recovery non-invasively. These results are promising; however, before we can translate them to humans, it is important to reproduce them in a more clinically relevant model. Indeed, SCIs do not lead to the same cellular events in mice and humans. In particular, SCIs in humans induce the formation of cystic cavities. That is why we propose here to validate the effects of rTSMS in a rat animal model in which SCI leads to the formation of cystic cavities after penetrating and contusive SCI. To do so, several techniques, including immunohistochemical, behavioral and MRI, were performed. Our results demonstrate that rTSMS, in both SCI models, modulates the lesion scar by decreasing the formation of cystic cavities and by improving axonal survival. Moreover, rTSMS, in both models, enhances functional locomotor recovery. Altogether, our study describes that rTSMS exerts positive effects after SCI in rats. This study is a further step towards the use of this treatment in humans
Inhibition of ADAMTS-4 Expression in Olfactory Ensheathing Cells Enhances Recovery after Transplantation within Spinal Cord Injury
International audienceSpinal cord injury (SCI) induces permanent loss of sensitive and motor functions below the injury level. To date, a wide variety of cells has been used as biotherapies to cure SCI in different animal paradigms. Specifically, olfactory ensheathing cells (OECs) is one of the most promising. Indeed, OECs have been shown to enhance recovery in many animal studies. Moreover, OECs transplantation has been applied to a paraplegic patient and have shown beneficial effects. However, it has been reported that the significant level of recovery varies among different patients. Therefore, it is of primary importance to enhance the regenerative efficiency of OECs for better translations. Recently, it has been shown that inhibiting ADAMTS4 expression in glial cells in vitro increases their synthesis of neurotrophic factors. We hypothesized that the expression of neurotrophic factors secreted by OECs can be increased by the deletion of ADAMTS4. Taking advantage of ADAMTS4-/- mouse line, we produce ADAMTS4 deficient primary OEC cultures and then we investigated their regenerative potential after SCI. By using quantitative polymerase chain reaction, bioluminescence imaging, measurement of locomotor activity, electrophysiological studies, and immunohistochemistry, our results show that ADAMTS4-/- olfactory bulb OEC (bOECs) primary cultures upregulate their trophic factor expression in vitro, and that the transplantation of ADAMTS4-/- bOECs in a severe SCI model increases functional recovery and tissue repair in vivo. Altogether, our study reveals, for the first time, that primary bOEC cultures transplantation can be potentialized by inhibition of the expression of ADAMTS4
FoxJ1 regulates spinal cord development and is required for the maintenance of spinal cord stem cell potential
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RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate
Ependymal cells reside in the adult spinal cord and display stem cell properties in vitro. They proliferate after spinal cord injury and produce neurons in lower vertebrates but predominantly astrocytes in mammals. The mechanisms underlying this glial-biased differentiation remain ill-defined. We addressed this issue by generating a molecular resource through RNA profiling of ependymal cells before and after injury. We found that these cells activate STAT3 and ERK/MAPK signaling post injury and downregulate cilia-associated genes and FOXJ1, a central transcription factor in ciliogenesis. Conversely, they upregulate 510 genes, seven of them more than 20-fold, namely Crym, Ecm1, Ifi202b, Nupr1, Rbp1, Thbs2 and Osmr—the receptor for oncostatin, a microglia-specific cytokine which too is strongly upregulated after injury. We studied the regulation and role of Osmr using neurospheres derived from the adult spinal cord. We found that oncostatin induced strong Osmr and p-STAT3 expression in these cells which is associated with reduction of proliferation and promotion of astrocytic versus oligodendrocytic differentiation. Microglial cells are apposed to ependymal cells in vivo and co-culture experiments showed that these cells upregulate Osmr in neurosphere cultures. Collectively, these results support the notion that microglial cells and Osmr/Oncostatin pathway may regulate the astrocytic fate of ependymal cells in spinal cord injury