Study of therapeutic effects of ecto-mesenchymal olfactory stem cells transplantation and respiratory/locomotric rehabilitation after compressive spinal cervical lesion in the rat

Le SNC est doté de faibles capacités régénératives intrinsèques. Ses lésions se traduisent par l’apparition d’incapacités irréversibles invalidantes. Les traumas spinaux cervicaux (C1-C2) représentent la majorité des cas. Ils détruisent, les voies bulbo-spinales respiratoires interrompant ainsi les connexions synaptiques entre les pré-motoneurones et le pool de motoneurones phréniques causant un dysfonctionnement diaphragmatique. Ces lésions atteignent aussi les voies pyramidales commandant les neurones moteurs situés dans l'élargissement cervical qui innervent les extrémités supérieures impliquées dans les fonctions motrices, Les symptômes respiratoires consistent en une capacité vitale réduite et des infections pulmonaires. Les symptômes musculo-squelettiques comprennent la paraplégie, l'hémiplégie, l'hémiparésie, la tétraplégie. Peu d'études sont consacrées à l’évaluation du potentiel thérapeutique des cellules souches ecto-mésenchymateuses olfactives (OEMSCs) dans des modèles lésionnels chez les rongeurs. Celui-ci a été évalué sur notre modèle lésionnel compressif en C2 qui induit un déficit respiratoire et locomoteur persistant, reproductible et quantifiable. Elles présentent de fortes capacités prolifératives et neurogéniques et ne présentent aucun facteur co-morbide. Ces rats syngéniques nous ont permis d’évaluer la faisabilité, d’éviter l’utilisation d’anti rejet et de permettre une bonne intégration des OEMSCs dans le tissu hôte. Leur transplantation facilite une récupération substantielle des fonctions respiratoires et locomotrice, réduit la zone lésionnelle et l'inflammation et favorise l’axogénèse suite à une lésion cervicale en C2.The CNS has weak intrinsic regenerative capabilities. Its lesions result in the appearance of irreversible incapacitating disabilities. Cervical spinal trauma (C1-C2) represents the majority of cases. They destroy the bulbo-spinal respiratory tract thus interrupting the synaptic connections between the pre-motoneurons and the phrenic motor neuron pool causing diaphragmatic dysfunction. These lesions also reach the pyramidal pathways controlling the motor neurons located in cervical enlargement that innervate the upper extremities involved in the motor functions. Respiratory symptoms consist of a reduced vital capacity and pulmonary infections. Musculoskeletal symptoms include paraplegia, hemiplegia, hemiparesis, quadriplegia. Few studies are devoted to assessing the therapeutic potential of olfactory ecto-mesenchymal stem cells (OEMSCs) in rodent models of injury. This one was evaluated on our model compressive lesion in C2 which induces respiratory and locomotor deficit persistent, reproducible and quantifiable. They have high proliferative and neurogenic capacities and have no co-morbid factor. The choice of a syngeneic strain allowed us to evaluate the feasibility, to avoid the use of anti rejection and thus to allow an integration of the OEMSCs in the host tissue. The transplantation of OEMSCs facilitates a substantial recovery of respiratory and locomotor functions, reduces lesion area and inflammation, and promotes axogenesis following cervical spinal cord injury in C2

A new model of upper cervical spinal contusion inducing a persistent unilateral diaphragmatic deficit in the adult rat

International audienc

Restorative respiratory pathways after partial cervical spinal cord injury: role of ipsilateral phrenic afferents

International audienc

Axotomized bulbospinal neurons express c-Jun after cervical spinal cord injury

In several central nervous system neuronal populations, axotomy triggers the upregulation of regeneration-associated genes such as c-Jun, which determines neurons ability to regenerate axon in a growth-permissive environment. We analyzed the expression of c-Jun in rat ventral medullary neurons after cervical hemisection in order to investigate their intrinsic regenerative potential. Maximal expression of c-Jun was observed 7 days after injury mainly in axotomized medullary neurons located in the gigantocellularis nucleus, the raphe nucleus and, although less intensively, in the rostral ventral respiratory group. This suggests that after high cervical injury, a large number of medullary neurons projecting to the spinal cord become competent for axonal regeneration, although this regenerating potential may not be equivalent between the various neuronal populations

Specific and artifactual labeling in the rat spinal cord and medulla after injection of monosynaptic retrograde tracers into the diaphragm

International audienc

A unique method for the isolation of nasal olfactory stem cells in living rats

International audienceStem cells are attractive tools to develop new therapeutic strategies for a variety of disorders. While ethical and technical issues, associated with embryonic, fetal and neural stem cells, limit the translation to clinical applications, the nasal stem cells identified in the human olfactory mucosa stand as a promising candidate for stem cell-based therapies. Located in the back of the nose, this multipotent stem cell type is readily accessible in humans, a feature that makes these cells highly suitable for the development of autologous cell-based therapies. However, preclinical studies based on autologous transplantation of rodent olfactory stem cells are impeded because of the narrow opening of the nasal cavity. In this study, we report the development of a unique method permitting to quickly and safely biopsy olfactory mucosa in rats. Using this newly developed technique, rat stem cells expressing the stem cell marker Nestin were successfully isolated without requiring the sacrifice of the donor animal. As an evidence of the self-renewal capacity of the isolated cells, several millions of rat cells were amplified from a single biopsy within four weeks. Using an olfactory discrimination test, we additionally showed that this novel biopsy method does not affect the sense of smell and the learning and memory abilities of the operated animals. This study describes for the first time a methodology allowing the derivation of rat nasal cells in a way that is suitable for studying the effects of autologous transplantation of any cell type present in the olfactory mucosa in a wide variety of rat models